True vasculitis in lupus nephritis.

Vascular lesions are encountered frequently in renal biopsy specimens of patients with systemic lupus erythematosus (SLE) and can present in a variety of morphologic forms. True renal lupus vasculitis (TRLV) is one of the rare vascular lesions associated with lupus nephritis that has been infrequently reported in the medical literature. The primary focus on glomerular pathology and collective classification of the vascular lesions under lupus vasculopathy is one of the reasons why this form of inflammatory vasculitis has been under-recognized as a separate disease entity. Here we have comprehensively reviewed the literature on renal vascular involvement in SLE for a better understanding of the epidemiology, morphologic features, pathogenesis, clinical course and treatment of TRLV. It can be morphologically differentiated from other forms of renal vascular lesions in lupus nephritis, i.e. arteriosclerosis, uncomplicated vascular immune deposits, non-inflammatory necrotizing vasculopathy, and thrombotic microangiopathy. Despite close similarities with antineutrophil cytoplasmic autoantibody associated vasculitis (AASV), there are certain morphological differences that warrant a thorough investigation of the possible pauci-immune mechanism of pathogenesis. The vasculitis follows a severe clinical course in general with rapid progression to renal failure, although favorable outcomes have been reported in certain cases. The standard use of steroids and cytotoxic drugs has yielded variable results in the treatment of TRLV. Current treatment modalities being used in lupus nephritis and AASV have been compared in this article with focus on drugs acting on the inflammatory cells implicated in TRLV pathogenesis.

New aspects of posttransplant nephrotic syndrome: clinicopathologic correlations with outcomes.

Although posttransplant nephrotic syndrome is frequent, its structural basis and prognosis have not been clearly defined. The biopsy findings of 54 patients with this disorder posttransplant, among 375 total renal transplant recipients engrafted during a 10-year period, were correlated with clinical follow-up data. The mean patient age was 41.7 +/- 12.3 years, female/male ratio 22/32, and cadaveric/living-related donor ratio 37/17. The nephrotic syndrome developed 3 to 91 months posttransplant. At the onset the mean values of serum creatinine was 2.9 +/- 1.8 mg/dL and proteinuria 4.5 +/- 0.8 g/d. The index biopsy findings showed chronic allograft nephropathy (CAN) in 33; de novo glomerulonephritis (GN) in 6, recurrent GN in 9, and undetermined GN in 6 who had an unknown primary renal disease. Among 21 follow-up biopsies during a mean of 44.3 +/- 28 months the CAN progressed but the GN remained the same. The treatment included augmented steroids alone (n = 1) or in combination with cyclophosphamide (n = 2) and with plasmapheresis (n = 1); angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) along (n = 5); calcium channel blockers (CCB) alone (n = 24); or the two types of drugs together (n = 22). Complete or partial remission was achieved in 8 and 5, respectively, but nephrotic syndrome recurred in 3 of these patients at 45.1 +/- 18 months later. Sustained remission was more likely in cases of GN (minimal change disease and IgA nephropathy) and ACEI-ARB treatment (P <.01). Graft failure, which occurred in 35 patients, correlated strongly with serum creatinine at onset, being significantly greater in patients with CAN (P <.005). Both remission of the nephrotic syndrome and graft survival were greater among patients with GN as compared to those with CAN.

Diagnosing primary and metastatic renal cell carcinoma: the use of the monoclonal antibody 'Renal Cell Carcinoma Marker'.

The diagnosis of primary or metastatic renal cell carcinoma (RCC) can be difficult, especially in small biopsies, because of the wide variety of histologic appearances and clinical presentations that RCC can assume. An immunomarker specific for RCC is currently not available. We tested the relevant diagnostic use of the Renal Cell Carcinoma Marker (RCC Ma), a monoclonal antibody, against a normal human proximal tubular brush border antigen. Immunostaining using RCC Ma and the avidin-biotin-peroxidase complex technique was performed on archival tissues from primary and metastatic tumors of renal or nonrenal origin. A total of 122 of 153 primary RCCs (79.7%) were positive [clear cell (84%), papillary (96%), chromophobe (45%), sarcomatoid (25%), and collecting duct (0%)], with > or =10% of tumor cells stained in 93% of cases. None of the 64 primary renal tumors other than RCC, including 15 oncocytomas, was positive. Fifteen of 146 (10.2%) nonrenal primary tumors were positive (5 of 17 breast tumors, 8 of 8 parathyroid adenomas, and 2 of 7 embryonal carcinomas). Forty-two of 63 (67%) metastatic RCCs were positive with > or =10% of cells being stained in 83% of them. Two of 108 (2%) metastases from tumors other than RCCs were positive, both of which were metastatic breast carcinomas; however, only 10% (2 of 19) of metastatic breast carcinomas were positive. RCC Ma is an excellent marker for primary RCC, which should facilitate its diagnosis in a small biopsy. Although RCC Ma remains highly specific (98%) for metastatic RCC, a negative result may not rule out metastatic RCC because of a rather low sensitivity and a focal staining pattern in some of the positive cases. RCC Ma may also facilitate the differential diagnosis between oncocytoma and other types of RCC when they are composed mostly of eosinophilic cells.

Nonlupus nephritides in patients with systemic lupus erythematosus: a comprehensive clinicopathologic study and review of the literature.

Renal biopsy specimens from patients with systemic lupus erythematosus (SLE) rarely show changes that are pathogenetically and morphologically unrelated to SLE. The morphology and behavior of these nonlupus nephritides are not well known. Two hundred fifty-two renal biopsies performed on 224 patients with SLE collected from 3,036 native kidney biopsies performed between 1975 and 1998 were reviewed, and those that showed nonlupus nephritides (index biopsies) were selected for studies. Thirteen biopsy specimens with nonlupus nephritides were identified in 13 patients, who belonged to 3 clinically distinct groups. Group I included 6 patients in whom SLE was diagnosed at the time of index biopsies. The index biopsies in these patients showed focal segmental glomerusclerosis (FSGS; 3 cases), Immunoglobulin (Ig) M nephropathy (1 case), and thin basement membrane disease (1 case). The diagnostic features for FSGS included segmental sclerosis involving at least 1 glomerulus, absence of lupus nephritis or other conditions that may cause nonspecific segmental sclerosis of glomeruli such as ischemia or nephrosclerosis, and nephrotic-range proteinuria. There was uniform, global, diffuse and marked thinning of the glomerular basement membrane in the case of thin basement membrane disease. Group II included 3 patients in whom SLE was diagnosed 2 to 9 years before the time of index biopsies and SLE was active at the time of biopsy. The index biopsies in these patients showed FSGS (2 cases) and hypertensive nephrosclerosis (1 case). Group III included 4 patients in whom SLE was diagnosed 5 to 36 years before the time of index biopsies and SLE was inactive at the time of biopsy. The index biopsies in these patients showed 1 case each of amyloidosis, FSGS, hypertensive nephrosclerosis, and allergic acute tubulointerstitial nephritis. Previous renal biopsies, performed in 5 patients, showed IgM nephropathy (1 case), diffuse proliferative lupus GN (1 case), focal proliferative lupus GN (1 case), and mesangial proliferative lupus GN (2 cases). Follow-up biopsies, performed in 3 patients, confirmed the diagnosis of FSGS (2 cases) and hypertensive nephrosclerosis (1 case) noted in the index biopsies. Nonlupus nephritides may occasionally be encountered in SLE patients, regardless of clinical or serologic disease activity. These renal lesions display a broad morphologic spectrum in which FSGS seems most frequent. Renal biopsy plays a crucial role in identifying these lesions, which may have prognostic and therapeutic implications distinct from those of lupus nephritis.

Renal cell apoptosis in chronic obstructive uropathy: the roles of caspases.

BACKGROUND: Apoptosis of tubular and interstitial cells is well documented in kidneys with chronic obstructive uropathy (COU) and probably plays an important role in the pathogenesis of this condition. The molecular control of apoptosis in COU remains poorly understood. Apoptosis in general is known to proceed initially along distinct pathways, which later converge into a common arm characterized by orderly activation of caspases. Caspases are cytosolic enzymes that belong to a 12-member family and serve as effector molecules for apoptosis. The role of individual caspases in mediating renal cell apoptosis in kidneys with COU is studied. METHODS: Kidneys were harvested from sham-operated mice and mice with COU created by left ureter ligation at days 4, 7, 15, 20, and 30. The following studies were performed: (1) determination of dried kidney weight; (2) in situ end labeling of fragmented DNA to detect apoptotic tubular and interstitial cells; (3) ribonuclease protection assay with specific anti-sense RNA probes for caspases 1, 2, 3, 6, 7, 8, 9, 11, and 12 to detect the expression of individual caspases; (4) immunostaining for caspases; and (5) assay for caspase 3. To assess the role of caspases in COU-associated renal cell apoptosis, the frequencies of apoptotic tubular and interstitial cells were separately quantitated for each experimental time point, and their patterns of variation were correlated with those of individual caspases. RESULTS: The obstructed kidneys showed progressive tissue loss (60% of control at day 15). Apoptosis of both tubular and interstitial cells was seen in obstructed kidneys. Tubular cell apoptosis peaked at four days after ureter ligation (13-fold of control), remained high between days 4 to 15, and thereafter decreased rapidly. Apoptotic interstitial cells were scanty initially, but gradually increased throughout the entire experiment. Apoptosis was minimal throughout the experiment in control and contralateral kidneys. In control and contralateral kidneys, caspases 2, 3, 6, 7, 8, and 9 mRNAs were expressed at low levels, whereas those for caspases 1, 11, and 12 were not detected. The obstructed kidneys displayed increased expression of all tested caspases. Caspases 1, 11, and 12 mRNAs were detected in obstructed kidneys in a common pattern characterized by a sharp increase at day 4, followed by a decrease until day 20, and a subsequent sharp increase until the end of the study at day 30. A similar pattern was noted for other caspases (2, 3, 6, 7, 8, and 9), which maximally reached twofold to fourfold that of controls. Immunostaining for caspases 1, 2, 3, 6, 7, 8, and 9 showed the same pattern characterized by focal and weak expression in proximal tubules of control or contralateral kidney, contrasting with increased staining in atrophic or dilated tubules of obstructed kidneys. Interstitial cells also displayed staining for several caspases, which paralleled the increasing density of interstitial cells toward the end of the experiment. Caspase-3 assay showed a marked increased activity in obstructed kidneys that reached fourfold and sevenfold of control at days 4 and 30, respectively. The rise and fall of caspase mRNAs between days 4 and 30 paralleled a similar fluctuation in tubular cell apoptosis. The subsequent increase of mRNAs was correlated with a continuous rise of interstitial cell apoptosis. CONCLUSIONS: Urinary obstruction in mice induces apoptosis of both tubular and interstitial cells in the affected kidney in a distinctive pattern that parallels an increased expression of caspases. This correlation suggests that these caspases mediate COU-associated renal cell apoptosis. Among the evaluated caspases, increased renal caspase 3 activity implies its central role in renal cell apoptosis associated with urinary obstruction.

Aspiration biopsy of osseous metastasis of retroperitoneal paraganglioma. Report of a case with cytologic features and differential diagnostic considerations.

BACKGROUND: Paragangliomas are uncommon tumors, only 10% of which are malignant, as evidenced by metastatic disease. It is rare for paraganglioma to present with symptomatic osseous metastases. CASE: A retroperitoneal paraganglioma presented in a 52-year-old man as painful metastases in the rib and vertebrae. Fine needle aspiration (FNA) of a lumbar vertebral lesion showed cells arranged singly and in loose clusters with fragile, vacuolated or finely granular cytoplasm, marked anisonucleosis and mitoses. Rare zellballen-type structures and intranuclear inclusions were present. Immunohistochemical studies of a subsequent FNA core biopsy of the retroperitoneal mass showed strong immunoreactivity with chromogranin and negative staining for keratin; that was helpful in differentiating this tumor from others in the differential diagnosis. CONCLUSION: The cytologic diagnosis of paraganglioma is difficult as these tumors exhibit a plethora of features that overlap those of many other neoplasms. The diagnosis can be confirmed with appropriate immunohistochemical studies of corresponding core biopsies.

Renal lymphoma. The diagnostic and therapeutic roles of fine-needle aspiration.

This study focused on 19 patients with renal lymphoma (RL) from whom 20 initial (1 patient with fine-needle aspiration [FNA] specimens of masses in both kidneys) and 1 repeated FNA specimen were obtained. Of the 19 patients, 10 had secondary RL, 8 primary RL, and 1 transplant RL. The FNA samples were studied by smears (all cases), tissues (11), phenotyping by immunostaining (13) or flow cytometry (4), and gene rearrangement (3). The final diagnoses included 1 T-cell lymphoma and 18 B-cell lymphomas. Of the 20 original specimens, 14 were reported as positive for lymphoma, 3 suggestive of lymphoma, 1 positive for transitional cell carcinoma, and 2 unsatisfactory. The follow-up specimen showed reactive changes. Tissue correlation, available in 11 cases, confirmed a positive cytodiagnosis (7), provided a final diagnosis in the cytologically inconclusive cases (3), or revised the misdiagnosis of transitional cell carcinoma from smears (1). The phenotyping elucidated the B vs T lineage of the lymphoma in all tested cases, confirmed the positive cytodiagnosis in 10 cases, confirmed the reactive cytodiagnosis in 1 case, and helped achieve a conclusive diagnosis in 2 cases suggestive of lymphoma. Gene rearrangement studies showed light chain restriction in the 2 tested cases. FNA has an essential role in treatment planning for RL. Although FNA usually is diagnostically conclusive, a high index of suspicion and awareness of atypical or misleading cytomorphologic features are important for a correct interpretation, especially for primary RL. Ancillary testing is essential for the diagnosis in problematic cases and lays the foundation for the differential diagnosis.

Cryptococcal osteomyelitis. Report of a case with aspiration biopsy of a humeral lesion with radiologic features of malignancy.

BACKGROUND: Osteomyelitis due to Cryptococcus neoformans typically exhibits lytic lesions on radiographs. Extensive periosteal reaction is an uncommon feature. CASE: A 68-year-old man presented with pain and swelling in the left elbow. Radiologic studies exhibited a lytic humeral lesion with extensive periosteal reaction, interpreted as a malignant neoplasm. Fine needle aspiration biopsy (FNA) revealed abundant cryptococcal organisms. CONCLUSION: Cryptococcus is an uncommon cause of lytic osseous lesions that may mimic malignant neoplasms. Extensive periosteal reaction may support a radiologic diagnosis of primary osseous malignancy in rare cases. FNA with examination of Diff-Quik-stained slides may be employed for distinguishing cryptococcal osteomyelitis from malignant tumors and for prompt identification of the organisms.

Mechanism of chronic obstructive uropathy: increased expression of apoptosis-promoting molecules.

BACKGROUND: We have demonstrated that renal tubular and interstitial cells undergo pronounced apoptosis during the course of chronic obstructive uropathy (COU). Apoptosis is a complex cellular process consisting of multiple steps, each of which is mediated by families of related molecules. These families may include receptor/ligand molecules such as Fas, Fas ligand, tumor necrosis factor receptor-1 (TNFR-1), and TNF-related apoptosis inducing ligand (TRAIL); signal transduction adapter molecules such as Fas-associated death domain (FADD), TNFR-1 associated death domain (TRADD), receptor-interacting protein (RIP), Fas-associated factor (FAF), and Fas-associated phosphatase (FAP); or effector molecules such as caspases. However, the mechanism of tubular cell apoptosis, as well as the pathogenetic relevance of these apoptosis-related molecules in COU, remains poorly understood. METHODS: Kidneys were harvested from sham-operated control mice and mice with COU created by left ureter ligation sacrificed in groups of three at days 4, 15, 30, and 45. To detect apoptotic tubular and interstitial cells, in situ end labeling of fragmented DNA was performed. To detect the expression of apoptosis-related molecules, ribonuclease protection assay was used with specific antisense RNA probes for Fas, Fas ligand, TNFR-1, TRAIL, FADD, TRADD, RIP, FAF, FAP, and caspase-8. Immunostaining for Fas, Fas ligand, TRAIL, TRADD, RIP, and caspase-8 was also performed. To assess the role of these molecules in COU-associated renal cell apoptosis, the frequencies of apoptotic tubular and interstitial cells were separately quantitated for each experimental time point, and their patterns of variation were correlated with those of apoptosis-related molecules. RESULTS: The obstructed kidneys displayed increased apoptosis of both tubular and interstitial cells. Tubular cell apoptosis appeared at day 4 after ureter ligation, peaked (fivefold of control) at day 15, and decreased gradually until the end of the experiment. In contrast, interstitial cell apoptosis sustained a progressive increase throughout the experiment. Apoptosis was minimal at all experimental time points for control and contralateral kidneys. Compared with control and contralateral kidneys, the ligated kidneys displayed a dynamic expression of mRNAs for many apoptosis-related molecules, which included an up to threefold increase for Fas, Fas ligand, TNF-R1, TRAIL, TRADD, RIP, and caspase-8, and an up to twofold increase for FADD and FAP, but there was little change for FAF. These mRNAs increased between days 4 and 15, decreased until day 30, but then increased again until day 45. The rise and fall of mRNAs between days 4 and 30 paralleled a similar fluctuation in tubular cell apoptosis in that period. The subsequent increase of mRNAs was correlated with a continuous rise of interstitial cell apoptosis. We demonstrated a positive immunostaining for Fas and Fas ligand in the tubular cells at early time points as well as in interstitial inflammatory cells at later time points. Although increased expression of TRAIL, TRADD, RIP, and caspase-8 was noted in tubular cells, there was no staining for these molecules in interstitial cells. CONCLUSION: The current study documents a dynamic expression of several molecules that are known to mediate the most crucial steps of apoptosis. It implicates these molecules in COU-associated renal cell apoptosis and in the pathogenesis of this condition. It also lays the foundation for interventional studies, including genetic engineering, to evaluate the molecular control of apoptosis associated with COU.

Osmotically relevant membrane signaling complex: association between HB-EGF, beta(1)-integrin, and CD9 in mTAL.

The integral membrane proteins cluster of differentiation-9 (CD9), beta(1)-integrin, and heparin-binding epidermal growth factor-like (HB-EGF) exist in association in many cell lines and are linked to intracellular signaling mechanisms. Two of the proteins (CD9 and beta(1)-integrin) are induced by hypertonicity, suggesting that their related signaling processes may be relevant to osmotic stress. The validity of this hypothesis rests upon coexpression and physical association between these molecules in nephron segments that are normally exposed to high and variable ambient osmolality. In this work, we show that CD9 and beta(1)-integrin are induced in rat kidney medulla after dehydration. Immunohistochemistry and immunoprecipitation studies show that CD9, HB-EGF, and beta(1)-integrin are coexpressed and physically associated in medullary thick ascending limbs (mTAL), nephron segments that are normally exposed to high and variable extracellular osmolality. Our findings are consistent with the existence of a cluster of integral membrane proteins in mTAL that may initiate or modulate osmotically relevant signaling pathways.

Expression of adhesion molecules in kidney with experimental chronic obstructive uropathy: the pathogenic role of ICAM-1 and VCAM-1.

BACKGROUND: Chronic obstructive uropathy induced by maintained unilateral ureter ligation in the rat is characterized morphologically by interstitial inflammation, interstitial fibrosis, and tubular atrophy. Infiltrating mononuclear inflammatory cells, particularly T lymphocytes and macrophages, may contribute to the progression of this lesion by mediating tubular injury and by the activation of interstitial fibroblasts, with resultant tubular atrophy and interstitial fibrosis, respectively. Altered expression and activation of adhesion molecules by leukocytes, vascular endothelial cells, and parenchymal cells likely contributes both to the infiltration of inflammatory cells into the tubulointerstitial compartment and to the interaction of activated inflammatory cells with parenchymal cells. METHODS: In the current study, we examined changes in the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in a 90-day model of maintained unilateral ureter ligation in male Sprague-Dawley rats. RESULTS: Rat kidneys showed constitutive expression of ICAM-1 mRNA and constitutive immunostaining for ICAM-1 in peritubular capillaries, glomeruli, and a small percentage of cortical tubules. Ureter ligation resulted in a rapid increase in ICAM-1 mRNA, which was almost 2-fold greater than those of the contralateral and control kidneys as early as 3 h and which was maintained at a 4- to 6-fold higher level in the ligated vs. contralateral kidneys throughout the entire 90-day time course. There was a marked increase in ICAM-1 immunostaining within the tubular epithelium, with up to 80% of both cortical and medullary tubular cross-sections showing strong apical immunostaining from day 6 to 25, with a subsequent decrease throughout the remainder of the experiment. ICAM-1 immunostaining in the expanding interstitium in the ligated kidneys showed a gradual increase throughout the duration of the experiment. In contrast, glomerular immunostaining for ICAM-1 was decreased in the ligated compared to the contralateral kidneys throughout the entire experiment. There was a later but prominent increase in VCAM-1 mRNA in ligated kidneys, which was first evident at 2 days and which was maintained 2- to 10-fold greater than the contralateral kidneys throughout the entire time course. VCAM-1 immunostaining increased in the expanding interstitium, but decreased in glomeruli in obstructed vs. contralateral kidneys. Tubular staining for VCAM-1 did not change after ureter ligation. CONCLUSION: Increased ICAM-1 and VCAM-1 may contribute to the prominent inflammatory cell infiltration in the chronic tubulointerstitial nephritis accompanying maintained unilateral ligation. Tubule expression of ICAM-1, which occurs during a similar time course as previously documented for tubular cell proliferation and especially tubular cell apoptosis in this model, may contribute to injurious interactions of activated inflammatory cells with tubular epithelium.

Unilocular retroperitoneal cyst of mesothelial origin presenting as a renal mass.

We report the first 2 cases, to our knowledge, of retroperitoneal cysts with features of mesothelial differentiation that clinically mimic renal masses. The first lesion occurred in a 71-year-old man who presented with flank pain. Ultrasound and magnetic resonance imaging studies showed a unilocular cystic structure arising from the upper pole of the left kidney. The second lesion was in a 44-year-old woman who presented with left flank pain. Imaging studies revealed an 8-cm hemorrhagic cyst at the lower pole of the left kidney. Histologic examination of the nephrectomy specimens in each case revealed a unilocular cyst with intracystic and pericystic hemorrhage. In each case, the cyst was lined by a single layer of cells with ample eosinophilic cytoplasm and benign nuclear features without mucinous or müllerian differentiation. Histochemical staining showed Alcian blue positivity on the cell surface, which was sensitive to hyaluronidase digestion. Intracytoplasmic mucin, however, was not detected. Immunostaining showed that the cyst lining cells were positive for keratin, vimentin, HBME-1, WT1, and thrombomodulin but negative for carcinoembryonic antigen, B72.3, Leu-M1, and BerEP4. The first case was positive for calretinin, whereas the second was negative. These findings support the mesothelial nature of the cysts.

Thin basement membrane disease with heavy proteinuria or nephrotic syndrome at presentation.

Thin basement membrane disease (TBMD) is a condition originally defined as diffuse thinning of the glomerular basement membrane (GBM) associated with hematuria in all patients. Although proteinuria has been described in up to 60% of patients with TBMD, it is almost always mild, with a 24-hour excretion mostly of less than 500 mg. We describe eight patients (four men and four women between 32 and 66 years of age) with TBMD who presented with heavy proteinuria or nephrotic syndrome. Among the seven cases with family history, hematuria was noted in five. All patients had a long history of microscopic hematuria, with episodic gross hematuria in two. Renal biopsies showed diffuse thinning of the GBM in each patient (mean between 185.3 x 29.8 nm and 232.6 x 34.5 nm versus control between 325 x 35 nm and 350 x 15 nm). Three cases showed thinning of GBM only (group I); the remaining five cases showed thinning of GBM associated with focal segmental glomerulosclerosis. All three patients of group I presented with nephrotic syndrome and normal renal function. Treatment with steroids resulted in remission of nephrotic syndrome in two, whereas nephrotic syndrome persisted in the untreated patient. Among the five patients in group II, nephrotic syndrome and normal renal function at presentation were noted in two, whereas the other three had heavy proteinuria (2.2, 2. 5, and 2.6 g/d, respectively) associated with mildly decreased renal function (serum creatinine 1.8, 1.3, and 1.5 mg/dL, respectively). At last follow-up, although the renal function was stable in all five, only the three who received steroid treatment had remission or marked improvement of proteinuria. Hematuria, however, persisted in all eight patients of both groups. Whether specific gene mutations are translated into structural changes responsible for both excessive GBM thinning and increased transcapillary permeability remains to be elucidated. Alternatively, the heavy proteinuria/nephrotic syndrome may not be related to TBMD, but rather is the manifestation of associated glomerular diseases. Follow-up, including a response to steroids, supports the latter hypothesis.

Prostatic adenocarcinoma diagnosed by urinary cytology.

Prostatic adenocarcinoma rarely may involve the urinary bladder. Prostatic adenocarcinoma and high-grade transitional cell carcinoma (TCC) may coexist and account for the malignant cells seen in urinary cytology. Differentiating prostatic adenocarcinoma cells from those of TCC is important for therapy but remains difficult. A 10-year retrospective search identified 250 patients with high-grade carcinoma in urinary cytology. Among them, 6 cases of tissue-documented prostate adenocarcinoma were identified. The cytologic features of these cases were compared with those of 15 similarly documented cases of high-grade TCC. By using these criteria, 2 additional cases of prostatic adenocarcinoma were diagnosed prospectively. An oval nucleus with smooth borders; fine, powdery, evenly distributed nuclear chromatin and a large prominent nucleolus when present; and lack of significant pleomorphism are most helpful to differentiate prostatic adenocarcinoma from high-grade TCC. Recognizing these cells may be the first clue for the diagnosis of prostate adenocarcinoma.

Peritubular capillary loss is associated with chronic tubulointerstitial injury in human kidney: altered expression of vascular endothelial growth factor.

Chronic tubulointerstitial injury (CTI) including tubular atrophy and interstitial fibrosis represents one major determinant for the progression of chronic renal disease regardless of cause. Although peritubular capillaries (PTCs) are essential to maintain the normal structure and function of renal tubules, little is known about the role of PTCs in the development of CTI. The integrity of PTCs seems to be regulated by growth factors. Vascular endothelial cell growth factor (VEGF) has recently been recognized as a potent regulator of angiogenesis, vascular survival, and vascular permeability. Knowledge of the role of VEGF in renal disease is still rudimentary, and its role in CTI has not been explored. We analyzed the morphologic changes of PTCs and correlated them with other morphologic parameters of CTI in 32 human kidneys with various types of chronic tubulointerstitial disease. The VEGF expression was immunohistochemically evaluated. Compared with normal kidney, PTC loss (41% to 55% of control) and reduced size of PTCs (55% to 88% of control) were noted in kidneys with CTI. The PTC density was positively correlated with the proximal tubular density (r = 0.66, P <.0001), proximal tubular size (r = 0.54, P <.001), and negatively correlated with interstitial volume (r = -0.84, P <.0001). Compared with normal kidney, where podocytes were the only cell type that constantly expressed VEGF, an interesting pattern of increased VEGF expression by renal tubules, especially morphologically intact or hypertrophic ones, was shared by all cases with CTI. Loss of VEGF in sclerotic glomeruli was noted. PTC injury is pathogenetically linked to tubular atrophy, tubular loss, and interstitial fibrosis in human kidneys with CTI and might be a key factor for the progression of chronic tubulointerstitial disease. The characteristic and uniform pattern of altered VEGF expression in kidneys with CTI may result from ischemia induced by PTC loss and represent a protective mechanism against further PTC injuries. HUM PATHOL 31:1491-1497.

Malignant chondroblastoma presenting as a recurrent pelvic tumor with DNA aneuploidy and p53 mutation as supportive evidence of malignancy.

We report a rare case of malignant chondroblastoma, which presented in a 47-year-old man as a recurrent tumor, 18 years following wide excision of a typical pelvic chondroblastoma. Radiologic studies of the recurrent tumor showed a large, lytic, destructive lesion of the right pelvic bones and femur, with a pathologic fracture of the latter, a large pelvic soft tissue mass, and multiple pulmonary metastases. Biopsy tissue showed typical features of chondroblastoma, but also increased nuclear atypia, hyperchromasia, and pleomorphism, compared to the original tumor, and, most significantly, abnormal mitotic figures. Immunohistochemical studies of the recurrent tumor revealed p53 mutation and extensive proliferative activity, and flow cytometric studies showed DNA aneuploidy, none of which was present in the original tumor. The patient received chemotherapy and radiation, but died of disease eight months after presentation. We also review chondroblastoma in general, to assign this unusual lesion to a tumor subtype.

Caveolin-1 expression in clinically confined human prostate cancer: a novel prognostic marker.

We demonstrated previously elevated caveolin-1 expression in metastatic mouse and human prostate cancer cells both in vitro and in vivo. In this study, we analyzed its prognostic value for progression of clinically confined human prostate cancer. Immunohistochemical staining with a caveolin-1-specific antibody was performed on routinely processed paraffin sections from 189 radical prostatectomy specimens. Caveolin-1 immunoreactivity was evaluated in association with patients' age, race, preoperative prostate-specific antigen, clinical stage, and pathological features including Gleason score, extraprostatic extension, status of surgical margins, and time to disease progression after surgery. Positive caveolin-1 immunostaining was detected in 47 of the 189 cancers (25%) and correlated positively with Gleason score, positive surgical margin, as well as lymph node involvement (P = 0.0071, 0.0267, and 0.0399, respectively). In lymph node-negative cancers (n = 162), caveolin-1 immunoreactivity predicts a shorter time to disease progression after surgery (P = 0.0033, univariate analysis). Multivariate analyses that included caveolin-1 and other prognostic pathological markers identified positive caveolin-1 immunostaining as an independent predictor for time to disease progression (P = 0.0186). Thus, our study establishes caveolin-1 as a novel prognostic marker for clinically confined human prostate cancer.

Pheochromocytoma associated with neuroendocrine carcinoma. A new type of composite pheochromocytoma.

The coexistence of pheochromocytoma and other tumor types in a single adrenal gland has been rarely documented. This type of pheochromocytoma is designated "composite" or "mixed," depending on whether the pheochromocytoma and the nonpheochromocytoma components show the same embryologic origin. The nonpheochromocytoma components reported in the composite pheochromocytoma include ganglioneuroma, ganglioneuroblastoma, neuroblastoma, and malignant schwannoma. The components found in the mixed pheochromocytoma include adrenal cortical neoplasms and spindle cell sarcoma. We report a unique case of composite pheochromocytoma in which the nonpheochromocytoma element is a neuroendocrine carcinoma. The histologic and the immunohistochemical profiles of the 2 distinct components of this tumor were typical for those of pheochromocytoma and neuroendocrine carcinoma. This dual differentiation was also supported by ultrastructural findings. This case not only broadens the morphologic spectrum of composite pheochromocytoma but also provides some additional insight into the histogenesis of this rare but fascinating type of tumor.

Focal segmental glomerulosclerosis in a 32-year-old kidney allograft after 7 years without immunosuppression.

In kidney allografts, focal segmental glomerulosclerosis (FSGS) has been described as recurrent, de novo, or a histological variant of chronic transplant glomerulopathy. We describe a unique case of de novo FSGS in a renal transplant not accompanied by any feature of rejection in a patient who had not been immunosuppressed for several years. A 58-year-old woman received a histoidentical living-related kidney transplant for end-stage renal disease due to chronic pyelonephritis. Twenty-four years after the transplant she voluntarily discontinued all immunosuppressive medication. Seven years later she presented with nephrotic syndrome, mild renal failure, and positive serology for hepatitis C virus (HCV) antibody. The kidney transplant biopsy disclosed de novo FSGS. Features of acute or chronic rejection, including chronic transplant glomerulopathy, were not seen. The pathogenesis of this lesion is probably related to sustained and prolonged glomerular hyperfiltration; alternatively, HCV infection may have triggered or accelerated the appearance of FSGS.

Utilization of fine-needle aspiration in the diagnosis of metastatic tumors to the kidney.

Renal masses secondary to metastases are not common. Few comprehensive reviews exist, which consist primarily of autopsy and radiologic reports. The purpose of this study was to review the types and incidences of various neoplasms which metastasize to the kidney and to determine the usefulness of fine-needle aspiration (FNA) in diagnosing them. Two hundred and sixty-one radiologically guided FNAs of renal lesions over a 9-yr period were reviewed. The diagnoses of the 261 renal FNAs were as follows: 136 (52%) were malignant, 111 (43%) were benign, and 14 (5%) were unsatisfactory. Of the 136 positive FNAs, 28 (21%) revealed metastatic tumors. The overall incidence of renal FNAs displaying metastatic tumors was 11%. Among the 28 patients with metastases to the kidney, 23 patients were men and 5 were women, with the mean age being 58 yr. Twenty-five patients (89%) had prior history of a primary malignancy, including lung carcinoma (11 cases, 39%), lymphoma (8 cases, 29%), hepatocellular carcinoma (3 cases, 11%), and one case each of breast, pancreatic, and cervical cancer. In the remaining 3 patients (11%), with metastatic adenocarcinoma (2 cases) and squamous-cell carcinoma (1 case), the primary tumor site remained unknown despite an extensive clinical workup. Overall survival after FNA was poor, with a mean of 9.8 mo. FNA is useful in the diagnosis of masses in the kidney secondary to metastatic disease. This information is of clinical importance, principally in the exclusion of a primary malignancy, but also to avoid unnecessary surgery and to plan for subsequent patient care.