Printer Friendly

Nonneoplastic kidney diseases in adult tumor nephrectomy and nephroureterectomy specimens: common, harmful, yet underappreciated.

The current evaluation of tumor nephrectomy and nephroureterectomy specimens centers around the pathologic diagnosis, grade, and stage of the neoplasm. The application of synoptic reporting based on protocols and checklists from either the College of American Pathologists or the Association of Directors of Anatomic and Surgical Pathology serves to minimize the risk of missing any important pathologic parameters. (1,2) However, the assessment of the nonneoplastic kidney parenchyma is not a required parameter in either protocol, and concomitant nonneoplastic renal lesions are often overlooked during the pathologic assessment of these specimens. (3) In this review we will redirect the attention of the surgical pathologist to this important component.

Chronic kidney disease (CKD), previously known as chronic renal failure, is common and affects 1 in 9 adult patients, or roughly 20 million people in the United States. (4) Approximately 500 000 Americans have end-stage renal disease (ESRD), requiring renal replacement therapy (renal transplantation or dialysis), which cost $32 billion in 2004. (5) The risks for both cardiovascular6 and noncardiovascular (7) deaths are elevated in CKD patients, who typically die before progressing to ESRD. Of interest, up to 25% of renal cell carcinoma (RCC) patients have CKD prior to nephrectomy, and those with normal renal function are more likely to develop CKD after a radical nephrectomy procedure. (8,9) The substantial reduction of functional nephrons after partial or radical nephrectomy is often compounded by the concurrent effects of hypertension and diabetes, which are both important risk factors for developing RCC, (10-14) as well as CKD and, subsequently, ESRD. Therefore, it is not surprising that medical renal diseases are found in up to 60% of adult tumor nephrectomy specimens, of which most are attributed to diabetes or hypertension. (15)

Renal cell carcinoma comprises 2% to 3% of all adult malignancies. (16) With continuing advances in imaging, surgical techniques, and therapeutic regimens, renal neoplasms are detected earlier with improving survival rates, which will lead to more cures and longer periods free of disease or recurrence. (17) Although radical nephrectomy is the usual surgical treatment of RCC, nephron-sparing resections are more commonplace, as the preservation of renal function becomes an important consideration for the clinical outcome and quality of life in RCC survivors. The average 5-year survival rate for RCC patients is greater than 90%, 75% to 90%, and 59% to 70% for those with stages I, II, and III disease, respectively. (18) Similar survival rates are observed in patients with urothelial carcinomas of the upper urinary tract.19 According to the 2004 US Renal Data System, the average 60-, 70-, or 80-year-old with ESRD on dialysis has a life expectancy of 4.3, 3.1, or 2.2 years, respectively, which is substantially lower than the life expectancy of any RCC patient with stage I, II, or III disease. (20) A patient having both ESRD and stage I, II, or III urothelial or RCC would be more likely to die of his or her kidney disease than the underlying malignancy. These data underscore the significant morbidity of both CKD and ESRD.

Surgical pathologists have an opportunity during the evaluation of tumor nephrectomy and nephroureterectomy specimens to identify a variety of medical renal diseases. Similar to cancer, early detection of such lesions provides the best opportunity to intervene with appropriate therapies and to delay the progression of kidney injury. In fact, the evaluation of the nonneoplastic renal parenchyma becomes the most important determinant of clinical outcome when a benign renal or urothelial neoplasm is encountered. Based on the initial light microscopic examination, most renal diseases can be identified or suspected, which should prompt additional immunofluorescence (IF) and/or electron microscopy (EM). The surgical pathologist should adopt a systematic approach when evaluating the nonneoplastic renal parenchyma and be familiar with the characteristic histopathologic features of nonneoplastic renal diseases that commonly occur in nephrectomy and nephroureterectomy specimens.


Given that the best practices for the evaluation of the nonneoplastic renal parenchyma in tumor nephrectomy and nephroureterectomy specimens have not been established, we will provide our approach for evaluating this important component. Proper examination includes a systematic inspection of all 4 anatomic compartments of the kidney--the glomeruli, tubules, interstitium, and vessels, and requires the assistance of periodic acid-Schiff (PAS) and/or Jones methenamine silver (JMS) stains. To optimize visualization of the glomeruli and glomerular basement membranes (GBMs), these tissue sections should be 2 [Am in thickness rather than the 3- to 4-^m-thick sections that are typical of general surgical pathology specimens. To minimize the possibility of missing renal lesions, we suggest that the special stains should be available when the hematoxylin-eosin-stained sections of the neoplasm are being reviewed.

In general, the evaluation of well-preserved and non-ischemic glomeruli will be more informative, which should not be limited to a small number of glomeruli, because many glomerular lesions can be quite focal. If glomerular alterations, such as crescents, fibrinoid necrosis, GBM abnormalities (eg, thickening, "spike" formation, or double contours), mesangial sclerosis or mesangial hypercellularity (>2 mesangial cells per mesangial region away from the vascular pole in a 2-[micro]m-thick section), infiltration by inflammatory cells, or endocapillary proliferation, are present, direct IF (21,22) and/or EM (23,24) should be performed using formalin-fixed, paraffin-embedded tissue, albeit with generally less sensitivity for IF microscopy and processing/preservation artifact for EM. When direct IF microscopy is performed on the paraffin tissue sections, we routinely stain for immunoglobulin (Ig) G, IgA, IgM, [kappa] and [lambda] light chains, and albumin. In our laboratory, IF staining of paraffin sections for the complement components, C3c and C1q, has not been useful, but this contrasts with the experience of others.22 Immunohistochemistry for immunoglobulins and complement components is another technique that can be performed on paraffin tissue sections and has been more widely used in Europe. (25,26) The vascular compartment should be examined for the presence of intimal fibrosis, fibrinoid necrosis or vasculitis, intraluminal thrombi, atheroemboli, or hyalinosis. The tubulointerstitial compartment will demonstrate various degrees of interstitial fibrosis and tubular atrophy that may correlate with the degree of arteriosclerosis. Histologic features of acute tubular injury (or acute tubular necrosis) may be present, but the diagnosis should be made with caution, because this may represent a preservation artifact and is a finding of uncertain clinical significance in the setting of nephrectomy. Generally, mild interstitial inflammatory mononuclear cell infiltrates often accompany areas of interstitial fibrosis and tubular atrophy and are considered nonspecific findings. When a prominent interstitial inflammatory infiltrate is present between well-preserved tubules with interstitial edema and tubulitis (lymphocytes present between the tubular basement membrane and tubular epithelial cells), this warrants the diagnostic consideration of acute interstitial nephritis. Rare cases of concurrent non-Hodgkin lymphoma have been reported (see below).

Evaluation of the nonneoplastic renal parenchyma immediately adjacent to the neoplasm should be avoided when possible. Depending on the size of the renal neoplasm, the immediate 3 to 5 mm of adjacent renal parenchyma may demonstrate secondary changes from compression by the tumor. Partial nephrectomy specimens may not provide the most representative sample of the nonneoplastic renal parenchyma. Despite this limitation, diagnostic findings within these suboptimal areas, including prominent vascular or glomerular abnormalities, such as nodular glomerulosclerosis, may still be identifiable.

For optimal results, direct IF microscopy should be performed on a sample of nonneoplastic renal parenchyma frozen in optimal cutting temperature compound and EM studies using tissue preserved in glutaraldehyde or paraformaldehyde-based fixatives. However, saving such samples for potential IF and EM studies on all tumor nephrectomy or nephroureterotectomy specimens would be quite time consuming and costly. From a practical perspective, another approach would be to preserve a portion of nonneoplastic renal parenchyma in appropriate fixatives for future IF and EM studies only if a clinical suspicion for a glomerular disease (proteinuria or hematuria with red blood cell casts) is known when grossing the specimen. In the only prospective study on this topic, additional IF and EM testing was performed on saved tissue in only 10 of 60 tumor nephrectomy specimens (16.7%), which resulted in 5 additional diagnoses (8.3%; 2 IgA nephropathy cases with mild IgA deposition detected by IF, 2 cases of thin GBM disease, and 1 case of renal immunoglobulin light chain amyloidosis). (15) Given that additional IF and EM studies will be unnecessary in more than 80% of cases, saving tissue in all tumor nephrectomy specimens would not be cost effective. We believe that careful evaluation of the tissue sections by light microscopy with the aid of special stains is sufficient as the initial screen to dictate whether additional IF or EM studies are necessary. Based on our suggested algorithm, the diagnoses of early IgA or membranous nephropathy (MN) might be missed if no significant histologic glomerular alterations, such as mesangial hypercellularity or GBM thickening, were present. However, if a clinical history of persistent hematuria or proteinuria after nephrectomy were available, a retrospective analysis of the paraffin-embedded tissue block by IF, immunohistochemistry, and/or EM could still be performed at a later time and should establish the diagnosis of MN or IgA nephropathy (IgAN). By this approach, the diagnoses of thin GBM disease may be suspected but could not be firmly established using formalin-fixed, paraffin-embedded tissue. (23)


If either the College of American Pathologists or Association of Directors of Anatomic and Surgical Pathology synoptic reporting system is used in clinical practice, the evaluation of the nonneoplastic kidney parenchyma is not currently required in either protocol for tumor nephrectomy or nephroureterectomy specimens. We recommend adding this pathologic parameter to surgical pathology reports when diagnosing an urothelial carcinoma of the renal pelvis/ureter or RCC. When making a benign diagnosis in these specimens, synoptic reports may not be used, and other reminders may be necessary to minimize overlooking a concomitant nonneoplastic kidney disease. Establishing a system to order PAS and/or JMS special stains automatically when the specimen is processed for microscopic evaluation could be a possible solution.


Diabetes mellitus affects more than 20 million Americans and is the most common cause of ESRD in the United States.27 Approximately one third of diabetic patients will develop diabetic nephropathy (DN), which is associated with high morbidity and mortality. Diabetes is an established risk factor for developing RCC14,28 and is present in approximately 10% to 20% of RCC patients. (8,29) Pathologic features of DN are seen in up to 20% of tumor nephrectomy specimens. (3,15)

Diabetic nephropathy demonstrates a constellation of histopathologic changes affecting all 4 anatomic compartments of the kidney. Initially, the glomeruli become enlarged. Diffuse thickening of both the tubular and glomerular basement membranes gradually develops. Diffuse mesangial matrix deposition (or sclerosis) is found in varying degrees of severity and may be difficult to identify in the early stages (Figure 1, A). More advanced cases develop nodular mesangial sclerosis (or nodular glomerulosclerosis), also known as Kimmelstiel-Wilson nodules (Figure 1, B). These acellular nodules may reveal layering or a lamellated appearance. Mesangiolysis (dissolution and fraying of the matrix) with aneurysmal dilatation of the glomerular capillaries also may be present. Sometimes, mesangial nodules and aneurysmal dilation of the capillaries can still be appreciated within globally sclerotic glomeruli using the PAS or JMS stains. Additional characteristic features of DN are hyalinosis or insudative lesions (fibrin caps and capsular drops) that represent localized collections of plasma proteins. Fibrin caps represent accumulations of hyaline within glomerular capillaries that may obliterate the lumen. Capsular drops are accumulations of similar hyaline material between the glomerular parietal epithelial cells and Bowman capsule. The hyaline is PAS positive with a homogeneous staining quality that has a staining intensity similar to that of the GBM. This hyaline can also be present within the arterioles in a subendothelial location, which may be segmental or circumferential. Vascular disease may be advanced and widespread in DN. Intimal fibrosis is often observed in the larger arteries. Characteristic subendothelial hyalinosis involves both the afferent and efferent glomerular arterioles, but the appropriate tissue section through the vascular pole to visualize both arterioles is uncommon. Immunofluorescence microscopy typically demonstrates generally weak linear staining of the glomerular and tubular basement membranes, with similar intensities for both IgG and albumin, but this staining pattern is not specific for DN and also can be seen in the setting of hypertension and renal allografts. The EM features of DN are nonspecific and should confirm the light microscopic features, such as thickening of the GBM and increased mesangial matrix deposition. Occasionally, this matrix can have a vague fibrillar appearance, which has been termed diabetic fibrillosis and should not be mistaken for the fibrils of amyloid (10-12 nm in thickness) or fibrillary (roughly 20 nm in thickness) glomerulonephritis (GN). There is no single histopathologic feature that is pathognomonic for DN, but the constellation of the aforementioned features is highly suggestive of this important and common diagnostic entity.

Although nodular glomerulosclerosis (or nodular mesangial sclerosis) is a characteristic feature for DN, this finding is not specific and should provoke consideration of other entities, including renal amyloidosis, monoclonal immunoglobulin deposition disease, fibrillary GN, and immunotactoid glomerulopathy. A Congo red stain is used to help establish the diagnosis of renal amyloidosis, and the other entities can be diagnosed with the aid of IF and/or EM. Also, cases of idiopathic nodular glomerulosclerosis in association with hypertension and smoking have been reported in patients without diabetes. (30,31) Therefore, the pathologic diagnosis of DN should never be made without first establishing or confirming the clinical diagnosis of diabetes.

Bijol et al (15) found that nodular glomerulosclerosis (defined in their study as containing prominent Kimmelstiel-Wilson nodules) in tumor nephrectomy specimens was predictive of significantly decreased renal function within 6 months after surgery. Strict blood glucose control is the mainstay of therapy for both type 1 and type 2 diabetes. Long-term normoglycemia can halt the progression of DN, and possibly reverse the process of mesangial expansion. (32) Thus, diagnosing DN at any stage is important so that preventive measures or proper therapy can be administered.


Arterionephrosclerosis (also called hypertensive nephropathy/nephrosclerosis) is the most common finding in adult tumor nephrectomy specimens. The term benign has been used to qualify this entity, but it should be avoided because this injury process can be quite harmful and frequently leads to ESRD. We prefer using the descriptive term of arterionephrosclerosis because the clinical history of hypertension may not always be available at the time of pathologic evaluation.

Hypertension affects roughly 25% of the US adult population and is the second most common cause of ESRD in the United States. (27) Depending on the study, 25% to 60% of RCC patients are hypertensive. (8,29,33) Bijol et al (15) reported that 37% of nephrectomy specimens demonstrated mild to severe arterial and arteriolar sclerosis with minimal parenchymal changes, and an additional 22% of specimens demonstrated more severe vascular changes with parenchymal scarring. The pathologic diagnosis of arterionephrosclerosis is based on a constellation of nonspecific histopathologic features. The gross appearance of the kidney shows granularity of the capsular surface, which corresponds to the light microscopic glomerular and tubulointerstitial scarring due to this vascular injury. Additional light microscopic features include proliferative and fibrotic intimal thickening with narrowing of the arteries that may be accompanied by replication of the internal elastic lamina. Subendothelial hyalinosis affecting primarily the afferent but not efferent glomerular arterioles is often observed. Early glomerular changes are initiated by ischemic injury to the glomerulus with thickening and wrinkling of the basement membranes, usually in a global distribution along with thickening and fraying of Bowman capsule (Figure 2, A). Collagen gradually accumulates in the urinary space and compresses the shrunken glomerular tufts until eventually the entire glomerulus is sclerotic (Figure 2, B). Globally sclerotic glomeruli (global glomerulosclerosis) may be arranged in wedge-shaped zones of chronic ischemic injury of the outer cortex if the blood flow of larger renal arteries is compromised (Figure 2, C). Global glomerulosclerosis is associated frequently with tubular atrophy and interstitial fibrosis of the surrounding parenchyma because the blood exiting the efferent glomerular arteriole supplies the adjacent peritubular capillaries. Progressively more glomeruli are involved until the process results in ESRD with few residual intact nephrons. In advanced arterionephrosclerosis, there may be glomerular enlargement and superimposed focal segmental glomerulosclerosis, which has been postulated to be secondary to overloading the decreasing numbers of functional nephrons.

There are no pathognomonic histopathologic features for arterionephrosclerosis. In the absence of an immune complex-mediated injury, the combination of global glomerulosclerosis, interstitial fibrosis and tubular atrophy, and arteriosclerosis is consistent with this diagnosis. Given that global glomerulosclerosis involving more than 20% of glomeruli is predictive of worsening of renal function 6 months after nephrectomy, (15) an estimated percentage of global glomerulosclerosis is an important feature to report.


Thrombotic microangiopathy (TMA) with predominantly chronic features is found in up to 5% of tumor nephrectomy specimens. (15) Typical clinical signs include microangiopathic hemolytic anemia and thrombocytopenia. The pathologic finding of TMA can occur in a number of clinical settings, including but not limited to thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, malignant hypertension, scleroderma, preeclampsia, antiphospholipid antibody syndrome, radiation nephritis, drug toxicity, and disseminated intravascular coagulation. Thrombotic microangiopathy also has been associated with a variety of malignancies, including RCC. (34,35) Correlation with the clinical history is necessary to establish the correct etiology of TMA.

In the acute phase of TMA, fibrin thrombi may be observed within glomerular capillaries and extraglomerular vessels. The affected vascular structure often has a distended appearance, which is a subtle feature that may be useful to distinguish from capillaries that are simply congested by red blood cells. Red blood cell fragments (erythrocytolysis) may be present within the intima of affected arterioles or arteries. A Masson trichrome stain can highlight the thrombi in bright red. An immunohistochemical stain for CD61, a platelet marker, can also be used to confirm the presence of these thrombi. Glomerular capillaries may appear bloodless because of prominent swelling of the endothelial cells and obliteration of the lumina. Mesangiolysis as well as capillary aneurysm formation may be present. As the endothelial cell injury persists, the glomerular capillary walls become thickened by expansion of the subendothelial zone, eventually resulting in duplication (or double contours) of the GBMs in the chronic phase of TMA, which is best seen with PAS and JMS stains (Figure 3). Arterioles demonstrate subendothelial expansion and thrombosis, which eventually progress to sclerotic lesions. A characteristic arterial lesion is mucoid intimal change. Prominent concentric intimal and smooth muscle cell hyperplasia of the arterioles or arteries (onion skinning) may also be present. Immunofluorescence microscopy can show staining for fibrinogen in thrombi, as well as nonspecific trapping of IgM and the complement components in involved glomerular capillaries and arteriolar vessel walls. Electron microscopy findings include subendothelial space widening of the endothelial cells and separation from the underlying GBM in acute injury, with duplication of the GBMs as a sign of chronicity.



The therapeutic regimen that is used frequently to treat RCC deserves further discussion. Most chemotherapeutic agents, including mitomycin C, gemcitabine, vincristine, doxorubicin, cyclophosphamide, cisplatin, and daunorubicin, have been associated with TMA. (36) In addition, recently developed pharmacologic agents used to treat RCC include inhibitors of vascular endothelial growth factor, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. These targeted inhibitors have improved survival rates for patients with cancer of the colon, lung, and breast, and are promising therapies for the treatment of advanced RCC. (37,38) Sunitinib and sorafenib are oral multireceptor tyrosine kinase inhibitors that act on vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-KIT. Their side effects on the kidney include a preeclampsia-like syndrome with hypertension and proteinuria (39) and acute in terstitial nephritis. (40) In addition, therapy with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, has been reported to cause TMA. (41-43) Temsirolimus, an inhibitor of mammalian target of rapamycin, is another potential pharmacologic agent for treating RCC. This class of agents acts on the mammalian target of rapamycin pathway and has been widely used in the transplantation setting, primarily with sirolimus (rapamycin). Kidney injury with TMA (44,45) or intratubular casts46 that may represent myoglobin (47) have been reported with sirolimus, but such injuries have yet to be described with temsirolimus. Careful evaluation of the nonneoplastic kidney parenchyma serves the alternate purpose of establishing a baseline prior to the use of these potentially nephrotoxic agents that typically are given after nephrectomy. Also, metastatic RCC may call for the neoadjuvant administration of these agents prior to surgery. (48) With the expanding use of targeted inhibitors against RCC, surgical pathologists should be familiar with the features of TMA when evaluating the nonneoplastic kidney parenchyma.


Although sickle cell disease is an uncommon cause of TMA, sickle cell nephropathy is worthy of additional attention given the association of renal medullary carcinoma with sickle cell trait and disease. (49) In patients with sickle cell disease, the gross examination of the renal medulla may show congestion of the vasa recta in the renal medulla. In advanced disease, the vasa recta may be reduced in number, and papillary necrosis may be present. Careful histologic examination may reveal sickled red blood cells within the arteries and glomerular capillaries. The presence of prominent hemosiderosis in the proximal tubular epithelial cells is characteristic of this injury, which can be confirmed with a Prussian blue iron stain. Iron deposition may also be present in glomerular visceral and parietal epithelial cells. Focal global or segmental glomerular scarring can be seen. Chronic TMA with a membranoproliferative pattern of injury is common, (50) and collapsing glomerulopathy with prominence of visceral epithelial cells also has been reported. (51) Electron microscopy findings include fibrillary inclusions within the sickled red blood cells that represent polymerized hemoglobin.


Atheroembolic disease has been reported in up to 2% of tumor nephrectomy specimens (15) and often occurs in patients with severe atherosclerotic disease. When the kidneys are involved, this disease can present with acute kidney injury or renal insufficiency. Atheroemboli may result spontaneously or as a complication of invasive vascular procedures. Light microscopy demonstrates cholesterol clefts within the lumen of affected vessels, which can range from glomerular capillaries to interlobular arteries and, rarely, large arcuate arteries. An acute lesion often has blood, fibrin, and perhaps multinucleated giant cells surrounding the cholesterol clefts, whereas a chronic atheroembolus is embedded within intimal proliferation and/or sclerosis. There is no specific therapy for atheroembolic disease, but it may explain any clinical presentation of renal insufficiency or acute kidney injury.


Renal amyloidosis affects approximately 3% of RCC patients. (52,53) Although typically observed with chronic inflammatory states, such as rheumatoid arthritis or ankylosing spondylitis, more than 40 reported cases of AA amyloidosis are associated with RCC and demonstrate systemic involvement. This differs from endocrine tumors, such as medullary thyroid carcinoma and pancreatic islet cell tumors, where the non-AA amyloid deposits are limited to the involved organ. Renal cell carcinoma is the most common epithelial tumor, comprising 30% of carcinomas associated with AA amyloidosis. (54) AA amyloidoses associated with urothelial carcinomas of the renal pelvis and bladder have also been reported. (54,55) Other amyloid cases associated with RCC include AL amyloidosis (15,56) and leukocyte chemotactic factor 2, (57) and an angiomyolipoma with an uncharacterized protein. (58)

Renal amyloidosis is characterized by the deposition of amorphous eosinophilic material within glomeruli and/or vessel walls (Figure 4, A). A range of glomerular injury can occur, including nodular glomerulosclerosis. When visualizing with the PAS stain, the deposits stain less pink compared with the adjacent GBMs. The Congo red stain confirms the presence of amyloid deposits, which stain red and show green birefringence under polarized light (Figure 4, B). Positive staining for serum amyloid A protein by immunohistochemistry confirms the diagnosis of AA amyloidosis (Figure 4, C). Immunofluorescence studies may identify monoclonal amyloid deposits for either [kappa] or X light chain, which would be diagnostic of AL amyloidosis. Randomly arranged fibrils measuring 10 to 12 nm in thickness are observed by EM (Figure 4, D); they are thinner than the fibrils of fibrillary GN (approximately 20 nm). The pathogenesis of RCC-associated AA amyloidosis is not well understood, but a relationship with the underlying renal neoplasm is implicated. Removal of the renal neoplasm generally leads to resolution of both proteinuria (59) and hepatic and splenic deposition of amyloid, but the glomerular deposits of amyloid may persist. (60) Recurrence of proteinuria could indicate the presence of recurrent or metastatic RCC.


Membranous nephropathy, also known as membranous glomerulopathy or membranous GN, is a common cause of adult-onset nephrotic syndrome. Approximately 10% of MN cases are associated with malignancy, which are typically carcinomas of the lung, gastrointestinal tract, and breast. (61-65) Of all immune complex-mediated glomerular injuries that have been reported in carcinoma patients, MN is the most frequently observed, but only 10 RCC-associated MN cases have been reported in the English language literature. (62,66-74)

The spectrum of glomerular injury in MN depends primarily on the extent of subepithelial immune complex deposition. Although cancer-associated MN has similar histopathologic features to idiopathic or primary MN, Lefaucheur et al (65) recently found that the majority of cancer-associated MNs were in the early stages of development, and many demonstrated increased leukocytes within the glomerular capillaries, which has been termed glomerulitis or glomerular capillaritis. This histologic finding is an indication for additional IF and EM studies. Fewer than 10% of these cases also demonstrated glomerular microthrombi or TMA, but RCC-associated MN was not identified in this study. At an early stage of MN, the glomeruli appear normal by light microscopy, and even PAS or JMS stains may not demonstrate any apparent GBM abnormalities. At more advanced stages, prominent thickening of GBMs with perpendicular projections of basement membrane material or subepithelial "spikes" separating immune complexes can be visualized with PAS and JMS stains (Figure 5, A). When sectioned en face, the GBM may demonstrate vacuolizations imparting a "Swiss cheese" appearance. To determine whether the GBM is thickened, the tubular basement membrane of a well-preserved tubule can be used as a reference point, but this should be done with caution because both the tubular and glomerular basement membranes may undergo pathologic thickening in diabetes and hypertension. Varying degrees of segmental and/or global glomerular scarring (glomerulosclerosis) may be present. Immunofluorescent staining for IgG (Figure 5, B), and often C3, reveals granular deposits along the glomerular capillary walls. Cancer-associated MN cases may demonstrate more intense IF staining for IgG1 and IgG2, (72) compared with more prominent IgG4 staining seen in idiopathic MN cases. (75) By EM, subepithelial electron-dense deposits will be seen with or without intervening basement membrane material or spikes, and the overlying podocytes show extensive foot process effacement (Figure 5, C).


The pathogenesis of cancer-associated MN is unclear, but the glomerular injury may be mediated by immune complexes composed of tumor-associated antigens. (76) Alternatively, malignancies can cause defects in immune regulation, and they may render the cancer patient more susceptible to the induction of antibodies against endogenous or exogenous antigens and the subsequent development of immune complex nephritis. (77,78)

The resolution of proteinuria after surgical resection alone has been reported for both nonrenal carcinomas (79) and RCC, (67,70,74) which suggests a causal relationship with MN. In one of these reports, nephrotic syndrome recurred and correlated with the presence of metastatic disease. (74)


IgA nephropathy is the most common primary GN worldwide, including in the United States. (80) IgA nephropathy has been encountered in 1.8%, (15) 2.5%, (81) and as high as 18% (82) of tumor nephrectomies. Additional cases of IgAN in association with RCC also have been reported. (83-86) The principal clinical manifestations include microscopic or gross hematuria, which is also a common clinical sign of urothelial or RCC. Proteinuria may also be present and is typically subnephrotic range (<3 g/24 hours).






Few histopathologic descriptions of RCC-associated IgAN cases are available in the literature. In general, the histologic spectrum of glomerular abnormalities in IgAN ranges from normal glomeruli to cellular crescent formation with fibrinoid necrosis. (87) There frequently is mesangial hypercellularity ranging from minimal to severe (Figure 6, A), and it often varies within the same specimen. There may also be exudative lesions with segmental or global endocapillary GN. The presence of segmental or global glomerular scarring would indicate chronicity. The diagnosis of IgAN depends on the immunolocalization of deposits containing IgA as the dominant or codominant reactant (Figure 6, B), with frequent reactivity for IgG, C3, and [kappa] and X light chains. EM shows electron dense deposits in primarily mesangial areas (Figure 6, C). Immune deposits in subendothelial or, rarely, in subepithelial locations may also be identified.

The pathogenesis of IgAN is not well understood, and its relationship with RCC remains unclear because both the disappearance and persistence of hematuria and proteinuria after removal of RCC have been reported. (82)


Membranoproliferative glomerulonephritis (MPGN) is a well-known manifestation of hepatitis C. (88) In the setting of malignancies, MPGN is often associated with non-Hodgkin lymphoma (89) and is less commonly observed with solid tumors, with isolated reports associated with carcinoma of the breast, lung, (90,91) stomach, (92) prostate, (93) bladder, (94) and, only rarely, kidney. (64,95,96) Membranoproliferative glomerulonephritis has also been reported in pediatric Wilms tumors. (97) Membranoproliferative glomerulonephritis is characterized by the accentuation of the lobular architecture of the glomerular tufts and duplication of the GBMs (Figure 7). Immune complexes confirmed by IF and EM are present in primarily subendothelial and mesangial areas, with occasional subepithelial deposits. To our knowledge, dense deposit disease (also known as MPGN type II) has only been reported after immunosuppressive chemotherapy for breast carcinoma, not RCC. (98) The pathogenesis of MPGN in the setting of malignancy is not understood and potentially may be related to tumor-associated antigens.


Pauci-immune necrotizing and crescentic GN has been described in association with malignancies, including lymphoma (99,100); carcinoma of the stomach, (101) lung, (102) bladder and prostate (103,104); RCC (105-110); and after administration of immunotherapy for RCC. (111,112) Necrotizing and crescentic GN (113) has also been reported in association with on cocytoma, which further underscores the importance of careful examination of the nonneoplastic kidney with this otherwise benign renal neoplasm. In a large study of Wegener granulomatosis, the most common malignancy was RCC in 7 patients (1.5%), of whom 5 had concurrent crescentic GN. (107) In contrast, larger systematic studies of nontumor kidney parenchyma have not identified pauci-immune crescentic GN. (3,15,81,82) Lesions are characterized by fibrinoid necrosis of glomerular tufts with proliferation of epithelial cells resulting in crescent formation (Figure 8). Periodic acid-Schiff or JMS stains may reveal gaps in the GBM. Prominent tubulointerstitial nephritis may be present. Periglomerular granulomatous inflammation is a non-specific finding, but isolated interstitial granulomas not associated with rupture of Bowman capsule or necrotizing arteritis are thought to be specific for Wegener granulomatosis or Churg-Strauss syndrome in the setting of crescentic GN. (114) Necrotizing arteritis is seen in up to 20% of cases. With the possible exception of interstitial granulomas, the renal pathologic features of Wegener granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, and renal limited vasculitis are indistinguishable. Most patients with pauci-immune crescentic GN in association with an underlying malignancy demonstrate positive anti-neutrophil cytoplasmic antibody titers, but a few anti-neutrophil cytoplasmic antibody-negative cases have been reported. (110,113) In rare instances, Wegener granulomatosis alone may present as a renal mass. (115,116)

The other pathologic entities that can lead to crescentic GN are anti-GBM disease and immune complex-mediated GNs that have been discussed previously (see above). Of these entities, anti-GBM disease is the least common, and there is one putative case in the medical literature in association with RCC. (117) The diagnosis of anti-GBM disease is established by the presence of strong linear IgG staining of the GBM, which will be substantially more intense than albumin.

Systemic vasculitis of extrarenal small and medium-sized arteries has been reported in association with an oncocytoma (118) and RCC. (119) A variable range of clinical outcomes from no response to complete remission of the vasculitic injury has been observed after resection of the renal neoplasm.


Focal segmental glomerulosclerosis (FSGS) is the most common primary cause of adult nephrotic syndrome. (120) Focal segmental glomerulosclerosis has been identified in up to 9% of tumor nephrectomies and is associated with hypertension, arteriosclerosis and parenchymal scarring, or pyelonephritis. (15,82) Ejaz et al (121) describe a patient with RCC who developed progressive renal dysfunction 1 year after unilateral nephrectomy due to probable primary FSGS, which was initially overlooked and identified retrospectively.

Idiopathic or primary FSGS is caused by injury of the glomerular podocytes and characteristically manifests with nephrotic syndrome. Secondary FSGS arises because of structural or functional renal alterations, which can be categorized into 3 broad categories: (1) a response to reduction of functional nephron mass due to primary glomerular or tubulointerstitial disease of vascular, infectious, immunologic, hereditary, or congenital origin; (2) secondary to glomerulonephritis, with the consequence of postinflammatory segmental glomerular scarring; and (3) secondary to hereditary basement membrane defects, such as Alport syndrome.

Focal segmental glomerulosclerosis is characterized by segmental consolidation with capillary occlusion or collapse of the glomerular tuft (Figure 9). Consolidated segments have foam cells, mononuclear inflammation, and accumulation of extracellular matrix. The affected segments also have prominence or proliferation of visceral epithelium, often with cytoplasmic proteinaceous droplets. A working morphologic classification has recently subdivided FSGS into the collapsing, tip lesion, cellular, perihilar, and not otherwise specified variants. (122) The collapsing variant should be distinguished from ischemic collapse, which typically has global shrinkage of the glomerular tufts, with wrinkling of the GBM, periglomerular fibrosis, and absence of podocyte hypertrophy or hyperplasia. Immunofluorescence microscopy may reveal nonspecific trapping of larger molecules like IgM, C3, and sometimes C1q in the sclerosed or hyalinized glomerular regions. Electron microscopy reveals variable effacement and occasional microvillous transformation of podocyte foot processes with or without podocyte detachment from the GBM. No pathologic features can definitively distinguish between primary and secondary forms of FSGS.

The pathogenic mechanisms of FSGS remain to be elucidated, but mutations in various podocyte proteins, including those of the slit diaphragm, can cause FSGS in animal models and humans. (123) Although FSGS is frequently found in association with RCC, this is likely secondary to the advanced parenchymal injury that is frequently present in tumor nephrectomy specimens or the coincidental occurrence of 2 common diseases. Although it is possible that FSGS could be a paraneoplastic manifestation of the underlying renal neoplasm, the removal of the neoplasm has not been demonstrated to improve the extent of proteinuria or delay the progression of renal dysfunction.


Minimal-change disease is characterized clinically by the presence of nephrotic syndrome or nephrotic-range proteinuria (>3 g per day). This podocyte injury, or podocytopathy, has been reported in association with a wide spectrum of neoplasms, including oncocytoma (124) and RCC. (78,125,126) The diagnosis is established by the presence of diffuse effacement of the podocyte foot processes as visualized by EM. Unless the clinical history of proteinuria is present, our algorithm for evaluating the nonneoplastic renal parenchyma might not detect minimalchange disease because we do not recommend that all specimens undergo evaluation by EM, which is necessary to establish this diagnosis. Minimal-change disease would be an important diagnostic consideration in the RCC patient with persistent proteinuria after nephrectomy. If the podocytopathy is related to the underlying RCC, then surgical resection should be the appropriate therapy.


Invariably, the glomerular compartment will get much attention during the evaluation of the nonneoplastic portion of kidney. However, the tubulointerstitial compartment may contain important pathologic findings. Variable degrees of interstitial fibrosis and tubular atrophy will be present in nearly all tumor nephrectomy specimens, which are often accompanied by a mixture of mononuclear inflammatory cells. When the inflammatory infiltrate is limited primarily to areas of scarring (interstitial fibrosis and tubular atrophy), then the inflammation is considered to be nonspecific. Atrophic tubules are characterized by thickened, wrinkled, duplicated, or frayed tubular basement membranes. The presence of an interstitial inflammatory infiltrate between well-preserved or nonatrophic tubules should raise the diagnostic consideration of acute interstitial nephritis. The findings of aggregates of eosinophils, interstitial edema, or tubulitis (lymphocytes present between the tubular basement membranes and epithelial cells) involving well-preserved tubules are helpful to supporting this diagnosis. Acute interstitial nephritis has been found to involve nearly 4% of tumor nephrectomy specimens. (15) Acute interstitial nephritis is often due to an allergic drug reaction, and the common culprits include antibiotics, diuretics, and nonsteroidal anti-inflammatory drugs.



During the examination of the tubulointerstitial compartment, the presence of a neoplastic hematopoietic process or lymphoproliferative disorder may be encountered. This entity is technically a neoplastic disease, which extends beyond the scope of this review. However, as the focus of this article is to avoid missing any important pathologic diagnoses that may be present in addition to the neoplasm in question, it is worth noting that RCC patients have an increased risk for developing a second primary malignancy, which includes carcinomas of the prostate, breast, colon, bladder, and non-Hodgkin lymphoma. These second malignancies may precede, occur synchronously, or occur after the identification of RCC. (127-129) Although a primary non-Hodgkin lymphoma of the kidney is rare, infiltration of the kidney by either lymphoma or leukemia is common and has been observed in up to 60% of patients at autopsy. (130) Infiltration of the kidney by both non-Hodgkin (89,131-134) and, rarely, Hodgkin lymphoma (135) has been reported in RCC patients and has been well reviewed. (129)


Xanthogranulomatous pyelonephritis has been described in association with both urothelial carcinoma and RCC. (136-139) Histologic features include a prominent mixture of predominantly foamy macrophages, lymphocytes, and plasma cells (Figure 10). The foamy macrophages should be distinguished easily from clear cell carcinoma. The pathogenesis is unclear, but bacterial infection, renal calculi, or other obstructive causes, such as a neoplasm, are usually present. Xanthogranulomatous pyelonephritis is generally a diffuse process, but focal involvement can rarely mimic a renal mass on imaging studies. (140)


This review article has focused primarily on the nonneoplastic kidney diseases that are commonly encountered in adult tumor nephrectomy specimens. However, theoretically, any nonneoplastic kidney disease could be present, and a few additional renal diseases that may or may not be related to the neoplastic process will be mentioned briefly in this section. Thin GBM disease has been identified in tumor nephrectomy specimens. (15) The diagnosis is established by measuring the GBMs using EM, and the World Health Organization criteria require that the average thickness should be less than 264 nm. (141) However, this diagnosis must be established on tissue that has been properly fixed for EM studies because processing paraffin-embedded tissues can artifactually thin the GBMs. (23) Persistent hematuria after nephrectomy in an RCC patient should raise the consideration of either thin GBM disease or an immune complex-mediated GN, such as IgAN.

We have experienced a single case of fibrillary GN associated with RCC (S. M. Meehan, unpublished data, November 2005). Light microscopic findings included expansion of the mesangial matrix by eosinophilic material and segmental scarring of the glomeruli. The IF microscopy showed granular staining in primarily mesangial areas for IgG and [kappa] and [lambda] light chains. A Congo red stain was negative, and the EM demonstrated randomly arranged and nonbranching fibrils, which had a similar appearance but were thicker (approximately 20 nm) than amyloid fibrils. The renal symptoms did not resolve after RCC resection, and a follow-up kidney biopsy several years later demonstrated worsening of glomerular and tubulointerstitial scarring. The pathogenesis of fibrillary GN remains unknown, but some cases are associated with hepatitis C and, rarely, with an underlying lymphoproliferative disorder (142); neither cause was found in our case.

Urate nephropathy can be observed in some patients with gout. This entity is characterized by the deposition of needle-shaped urate crystals within tubular lumina of distal tubules and collecting ducts in the renal medulla. We have observed recently urate nephropathy in an RCC patient with a long clinical history of gout (A. Chang, unpublished data, May 2008). Characteristic tophi and abundant deposition of urate crystals (Figure 11) were present within the renal medulla with secondary granulomatous interstitial nephritis. Acute elevations of serum uric acid levels can be observed in patients undergoing chemotherapy for leukemia or lymphoma, which can lead to acute urate nephropathy. Cryoablation of RCC is gaining use as a therapeutic option, and mild elevations of uric acid in urine samples from such patients have been reported,143 but to our knowledge this treatment modality has not led to documented cases of acute urate nephropathy.

Balkan endemic nephropathy, a familial form of chronic tubulointerstitial nephritis, is associated frequently with urothelial carcinoma of the upper urinary tract.144 The histologic features are nonspecific and include significant interstitial fibrosis and tubular atrophy, but reported cases have been limited to specific regions of southeastern Europe. Nonetheless, urothelial carcinomas of the upper urinary tract are frequently associated with chronic kidney disease, (145) so the nonneoplastic kidney parenchyma of these specimens in particular should be carefully reviewed.

Analgesic nephropathy has been historically associated with urothelial carcinoma (146,147) and RCC. (148) This entity, which is characterized by long-term usage of analgesic medications and the presence of interstitial inflammation with significant tubulointerstitial scarring, is now uncommon because of the withdrawal of phenacetin as a therapeutic agent.


End-stage kidneys are typically small and shrunken and demonstrate diffuse global glomerulosclerosis, severe interstitial fibrosis, tubular atrophy, tubular loss, and severe arteriosclerosis. It may be difficult or impossible to determine the original cause of ESRD in these extensively scarred kidneys. After 3 to 4 years of dialysis, most ESRD patients will develop acquired cystic disease. Numerous cysts of variable size typically demonstrate a proximal tubular phenotype and are lined by tubular epithelial cells, which are flattened or have small papillary projections. (149) End-stage renal disease patients with acquired cystic disease have an increased risk for developing RCCs that show a characteristic spectrum of histopathologic features. (150)


Nonneoplastic kidney diseases are commonly encountered in tumor nephrectomy and nephroureterectomy specimens, and their presence may negatively impact the progression of CKD and clinical outcome in these cancer patients. The surgical pathologist may have the first opportunity to identify these diseases, often at a point in time when appropriate intervention may delay the progression of CKD. When diagnosing a benign neoplasm, the status of the nonneoplastic kidney becomes the most important determinant of clinical outcome. Safeguards should be established to ensure that the nonneoplastic kidney parenchyma is not overlooked, which includes adding this important parameter to synoptic reports, obtaining PAS and/or JMS stains prior to microscopic evaluation of the neoplasm, and adopting a systematic approach to the evaluation of the light microscopic tissue sections. The identification of glomerular abnormalities, including mesangial hypercellularity or sclerosis, segmental scarring, crescent formation, glomerulitis, or glomerular basement membrane alterations should lead to additional IF and EM studies. Nearly any nonneoplastic kidney disease can be present in tumor nephrectomy and nephroureterectomy specimens by sheer chance, but DN and arterionephrosclerosis comprise most of these renal lesions. Additional injuries that may be related to the underlying neoplasm or its treatment regimen include TMA, AA amyloidosis, MN, IgAN, MPGN, pauci-immune crescentic GN, FSGS, minimal-change disease, acute interstitial nephritis, and xanthogranulomatous pyelonephritis. Surgical pathologists should be aware of the importance of both correctly classifying the underlying renal or urothelial neoplasm and the concomitant nonneoplastic kidney disease that is likely to be present in these specimens.

We thank Jose Manaligod, MD, for his careful review of this manuscript and insightful comments.


(1.) College of American Pathologists. Cancer protocols and checklists. http:// %2Fportlets%2FcontentViewer%2Fshow&_windowLabel = cntvwrPtlt&cntvwrPtlt% 7BactionForm.contentReference%7D=committees%2Fcancer%2Fcancer_ protocols%2Fprotocols_index.html&_state=maximized&_pageLabel=cntvwr. Updated January 2005. Accessed June 28, 2008.

(2.) Association of Directors of Anatomic and Surgical Pathology. Checklists and guidelines for surgical pathology reports of malignant neoplasms. http://www.adasp. org/Checklists/checklists.htm. Updated November 2003. Accessed June 27, 2008.

(3.) Henriksen KJ, Meehan SM, Chang A. Non-neoplastic renal diseases are often unrecognized in adulttumor nephrectomy specimens: areviewof246 cases. Am J Surg Pathol. 2007;31:1703-1708.

(4.) K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1-S266.

(5.) St Peter WL. Introduction: chronic kidney disease: a burgeoning health epidemic. J Manag Care Pharm. 2007;13:S2-S5.

(6.) Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-1305.

(7.) Fried LF, Katz R, Sarnak MJ, et al. Kidney function as a predictor of noncardiovascular mortality. J Am Soc Nephrol. 2005;16:3728-3735.

(8.) Huang WC, Levey AS, Serio AM, et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. Lancet Oncol. 2006;7:735-740.

(9.) Lau WK, Blute ML, Weaver AL, Torres VE, Zincke H. Matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc. 2000; 75:1236-1242.

(10.) Choi MY, Jee SH, Sull JW, Nam CM. The effect of hypertension on the risk for kidney cancer in Korean men. Kidney Int. 2005;67:647-652.

(11.) Chow WH, Gridley G, Fraumeni JF Jr, Jarvholm B. Obesity, hypertension, and the risk of kidney cancer in men. N Engl J Med. 2000;343:1305-1311.

(12.) Kirchner FK Jr. Incidence of renal cell carcinoma with hypertension. J Urol. 1978;119:579.

(13.) Melman A, Grim CE, Weinberger MH. Increased incidence of renal cell carcinoma with hypertension. J Urol. 1977;118:531-532.

(14.) Zucchetto A, Dal Maso L, Tavani A, et al. History of treated hypertension and diabetes mellitus and risk of renal cell cancer. Ann Oncol. 2007;18:596-600.

(15.) Bijol V, Mendez GP, Hurwitz S, Rennke HG, Nose V. Evaluation of the nonneoplastic pathology in tumor nephrectomy specimens: predicting the risk of progressive renal failure. Am J Surg Pathol. 2006;30:575-584.

(16.) Hock LM, Lynch J, Balaji KC. Increasing incidence of all stages of kidney cancer in the last 2 decades in the United States: an analysis of surveillance, epidemiology and end results program data. J Urol. 2002;167:57-60.

(17.) Kane CJ, Mallin K, Ritchey J, Cooperberg MR, Carroll PR. Renal cell cancer stage migration: analysis of the National Cancer Data Base. Cancer. 2008;113:78-83.

(18.) Tsui KH, Shvarts O, Smith RB, Figlin RA, deKernion JB, Belldegrun A. Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J Urol. 2000;163:1090-1095; quiz 1295.

(19.) Bolenz C, Fernandez MI, Trojan L, et al. Lymphovascular invasion and pathologic tumor stage are significant outcome predictors for patients with upper tract urothelial carcinoma. Urology. 2008;72:364-369.

(20.) Collins AJ, Kasiske B, Herzog C, et al. Excerpts from the United States Renal Data System 2004 annual data report: atlas of end-stage renal disease in the United States. Am J Kidney Dis. 2005;45:A5-A7,S1-S280.

(21.) Nasr SH, Galgano SJ, Markowitz GS, Stokes MB, D'Agati VD. Immunofluorescence on pronase-digested paraffin sections: a valuable salvage technique for renal biopsies. Kidney Int. 2006;70:2148-2151.

(22.) van der Ven K, Nguyen TQ, Goldschmeding R. Immunofluorescence on proteinase XXIV-digested paraffin sections. Kidney Int. 2007;72:896.

(23.) Collar J, Cattell V. Paraffin-processed material is unsuitable for diagnosis of thin-membrane disease. Nephron. 1995;69:187-188.

(24.) Nasr SH, Markowitz GS, Valeri AM, Yu Z, Chen L, D'Agati VD. Thin basement membrane nephropathy cannot be diagnosed reliably in deparaffinized, formalin-fixed tissue. Nephrol Dial Transplant. 2007;22:1228-1232.

(25.) Miller K. Immunohistochemistry on renal biopsies. http://www. Updated October 16, 1996. Accessed June 26, 2008.

(26.) Howie AJ, Gregory J, Thompson RA, Adkins MA, Niblett AJ. Technical improvements in the immunoperoxidase study of renal biopsy specimens. J Clin Pathol. 1990;43:257-259.

(27.) Foley RN, Collins AJ. End-stage renal disease in the United States: an update from the United States Renal Data System. J Am Soc Nephrol. 2007;18: 2644-2648.

(28.) Lindblad P, Chow WH, Chan J, et al. The role of diabetes mellitus in the aetiology of renal cell cancer. Diabetologia. 1999;42:107-112.

(29.) Hepps D, Chernoff A. Risk of renal insufficiency in African-Americans after radical nephrectomy for kidney cancer. Urol Oncol. 2006;24:391-395.

(30.) Alpers CE, Biava CG. Idiopathic lobular glomerulonephritis (nodular mesangial sclerosis): a distinct diagnostic entity. Clin Nephrol. 1989;32:68-74.

(31.) Markowitz GS, Lin J, Valeri AM, Avila C, Nasr SH, D'Agati VD. Idiopathic nodular glomerulosclerosis is a distinct clinicopathologic entity linked to hypertension and smoking. Hum Pathol. 2002;33:826-835.

(32.) Bilous RW, Mauer SM, Sutherland DE, Najarian JS, Goetz FC, Steffes MW. The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependentdiabetes. N Engl J Med. 1989;321:80-85.

(33.) Shirasaki Y, Tsushima T, Nasu Y, Kumon H. Long-term consequence of renal function following nephrectomy for renal cell cancer. Int J Urol. 2004;11:704-708.

(34.) Kwaan HC, Gordon LI. Thrombotic microangiopathy in the cancer patient. Acta Haematol. 2001;106:52-56.

(35.) Levi M. Cancer and thrombosis. Clin Adv Hematol Oncol. 2003;1:668-671.

(36.) Nadir Y, Hoffman R, Brenner B. Drug-related thrombosis in hematologic malignancies. Rev Clin Exp Hematol. 2004;8:E4.

(37.) Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125-134.

(38.) Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124.

(39.) Patel TV, Morgan JA, Demetri GD, et al. A preeclampsia-like syndrome characterized by reversible hypertension and proteinuria induced by the multitargeted kinase-inhibitors-sunitinib and sorafenib. J Natl Cancer Inst. 2008;100:282-284.

(40.) Khurana A. Allergic interstitial nephritis possibly related to sunitinib use. Am J Geriatr Pharmacother. 2007;5:341-344.

(41.) Frangie C, Lefaucheur C, Medioni J, Jacquot C, Hill GS, Nochy D. Renal thrombotic microangiopathy caused by anti-VEGF-antibody treatment for metastatic renal-cell carcinoma. Lancet Oncol. 2007;8:177-178.

(42.) Roncone D, Satoskar A, Nadasdy T, Monk JP, Rovin BH. Proteinuria in a patient receiving anti-VEGF therapy for metastatic renal cell carcinoma. Nat Clin Pract Nephrol. 2007;3:287-293.

(43.) Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358:1129-1136.

(44.) Barone GW, Gurley BJ, Abul-Ezz SR, Gokden N. Sirolimus-induced thrombotic microangiopathy in a renal transplant recipient. Am J Kidney Dis. 2003;42: 202-206.

(45.) Crew RJ, Radhakrishnan J, Cohen DJ, et al. De novo thrombotic microangiopathy following treatment with sirolimus: report of two cases. Nephrol Dial Transplant. 2005;20:203-209.

(46.) Smith KD, Wrenshall LE, Nicosia RF, et al. Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use. J Am Soc Nephrol. 2003;14:1037-1045.

(47.) Pelletier R, Nadasdy T, Nadasdy G, et al. Acute renal failure following kidney transplantation associated with myoglobinuria in patients treated with rapamycin. Transplantation. 2006;82:645-650.

(48.) Margulis V, Matin SF, Tannir N, et al. Surgical morbidity associated with administration of targeted molecular therapies before cytoreductivenephrectomy or resection of locally recurrent renal cell carcinoma. J Urol. 2008;180:94-98.

(49.) Dimashkieh H, Choe J, Mutema G. Renal medullary carcinoma: a report of 2 cases and review of the literature. Arch Pathol Lab Med. 2003;127:e135-e138.

(50.) Bakir AA, Hathiwala SC, Ainis H, et al. Prognosis of the nephrotic syndrome in sickle glomerulopathy. A retrospective study. Am J Nephrol. 1987;7: 110-115.

(51.) Nasr SH, Markowitz GS, Sentman RL, D'Agati VD. Sickle cell disease, nephrotic syndrome, and renal failure. Kidney Int. 2006;69:1276-1280.

(52.) Dictor M, Hasserius R. Systemic amyloidosis and non-hematologic malignancy in a large autopsy series. Acta Pathol Microbiol Scand [A]. 1981;89:411-416.

(53.) Vanatta PR, Silva FG, Taylor WE, Costa JC. Renal cell carcinoma and systemic amyloidosis: demonstration of AA protein and review of the literature. Hum Pathol. 1983;14:195-201.

(54.) Azzopardi JG, Lehner T. Systemic amyloidosis and malignant disease. J Clin Pathol. 1966;19:539-548.

(55.) Ersoy A, Filiz G, Ersoy C, et al. Synchronous carcinomas of stomach and bladder together with AA amyloidosis. Nephrology(Carlton). 2006;11:120-123.

(56.) Somer TP, Tornroth TS. Renal adenocarcinoma and systemic amyloidosis. Immunohistochemical and histochemical studies. Arch Pathol Lab Med. 1985; 109:571-4.

(57.) Benson MD, James S, Scott K, Liepnieks JJ, Kluve-Beckerman B. Leukocyte chemotactic factor 2: a novel renal amyloid protein. KidneyInt. 2008;74:218-222.

(58.) Toyoda M, Kudo M, Ebihara Y. Amyloid deposition in renal angiomyolipoma. Pathol Int. 1999;49:180-184.

(59.) Karsenty G, Ulmann A, Droz D, Carnot F, Grunfeld JP. Clinical and histological resolution of systemic amyloidosis after renal cell carcinoma removal. Nephron. 1985;40:232-234.

(60.) Lowenstein J, Gallo G. Remission of the nephrotic syndrome in renal amyloidosis. N Engl J Med. 1970;282:128-132.

(61.) Bjorneklett R, Vikse BE, Svarstad E, et al. Long-term risk of cancer in membranous nephropathy patients. Am J Kidney Dis. 2007;50:396-403.

(62.) Burstein DM, Korbet SM, Schwartz MM. Membranous glomerulonephritis and malignancy. Am J Kidney Dis. 1993;22:5-10.

(63.) Eagen JW. Glomerulopathies of neoplasia. Kidney Int. 1977;11:297-303.

(64.) Lee JC, Yamauchi H, Hopper J Jr. The association of cancer and the nephrotic syndrome. Ann Intern Med. 1966;64:41-51.

(65.) Lefaucheur C, Stengel B, Nochy D, et al. Membranous nephropathy and cancer: epidemiologic evidence and determinants of high-risk cancer association. Kidney Int. 2006;70:1510-1517.

(66.) Cudkowicz ME, Sayegh MH, Rennke HG. Membranous nephropathy in a patient with renal cell carcinoma. Am J Kidney Dis. 1991;17:349-351.

(67.) Fujita Y, Kashiwagi T, Takei H, et al. Membranous nephropathy complicated by renal cell carcinoma. Clin Exp Nephrol. 2004;8:59-62.

(68.) Kapoulas S, Liakos S, Karkavelas G, Grekas D, Giannoulis E. Membranous glomerulonephritis associated with renal cell carcinoma. Clin Nephrol. 2004;62: 476-477.

(69.) Kerpen HO, Bhat JG, Feiner HD, Baldwin DS. Membranous nephropathy associated with renal cell carcinoma. Evidence against a role of renal tubular or tumor antibodies in pathogenesis. Am J Med. 1978;64:863-867.

(70.) Kuroda I, Ueno M, Okada H, et al. Nephrotic syndrome as a result of membranous nephropathy caused by renal cell carcinoma. Int J Urol. 2004;11: 235-238.

(71.) Nishibara G, Sukemi T, Ikeda Y, Tomiyoshi Y. Nephrotic syndrome due to membranous nephropathy associated with renal cell carcinoma. Clin Nephrol. 1996;45:424.

(72.) Ohtani H, Wakui H, Komatsuda A, et al. Distribution of glomerular IgG subclass deposits in malignancy-associated membranous nephropathy. Nephrol Dial Transplant. 2004;19:574-579.

(73.) Stein HD, Yudis M, Sirota RA, Snipes ER, Gronich JH. Membranous nephropathy associated with renal cell carcinoma. Am J Kidney Dis. 1993;22:352.

(74.) Togawa A, Yamamoto T, Suzuki H, et al. Membranous glomerulonephritis associated with renal cell carcinoma: failure to detect a nephritogenic tumor antigen. Nephron. 2002;90:219-221.

(75.) Haas M. IgG subclass deposits in glomeruli of lupus and nonlupus membranous nephropathies. Am J Kidney Dis. 1994;23:358-364.

(76.) Couser WG, Wagonfeld JB, Spargo BH, Lewis EJ. Glomerular deposition of tumor antigen in membranous nephropathy associated with colonic carcinoma. Am J Med. 1974;57:962-970.

(77.) Alpers CE, Cotran RS. Neoplasia and glomerular injury. Kidney Int. 1986; 30:465-473.

(78.) Ozawa T, Pluss R, Lacher J, et al. Endogenous immune complex nephropathy associated with malignancy I. Studies on the nature and immunopathogenic significance of glomerular bound antigen and antibody, isolation and characterization of tumor specific antigen and antibody and circulating immune complexes. Q J Med. 1975;44:523-541.

(79.) Yamauchi H, Linsey MS, Biava CG, Hopper J Jr. Cure of membranous nephropathy after resection of carcinoma. Arch Intern Med. 1985;145:2061-2063.

(80.) Nair R, Walker PD. Is IgA nephropathy the commonest primary glomerulopathy among young adults in the USA? Kidney Int. 2006;69:1455-1458.

(81.) Beaufils H, Fatte R, Aubert P, et al. Renal immunopathology in renal cell carcinoma. Virchows Arch A Pathol Anat Histopathol. 1984;404:87-97.

(82.) Magyarlaki T, Kiss B, Buzogany I, Fazekas A, Sukosd F, Nagy J. Renal cell carcinoma and paraneoplastic IgA nephropathy. Nephron. 1999;82:127-130.

(83.) Abu-Romeh SH, al-Adnani MS, Asfar S. Renal cell carcinoma presenting with acute renal failure and IgA glomerulonephritis. Nephron. 1988;50:169-170.

(84.) Tanaka K, Kanzaki H, Taguchi T. IgA glomerulonephritis in a patient with renal cell carcinoma. Nippon Jinzo Gakkai Shi. 1991;33:87-90.

(85.) Sessa A, Volpi A, Tetta C, et al. IgA mesangial nephropathy associated with renal cell carcinoma. Appl Pathol. 1989;7:188-191.

(86.) Jain S, Kakkar N, Joshi K, Varma S. Crescentic glomerulonephritis associated with renal cell carcinoma. Ren Fail. 2001;23:287-290.

(87.) Haas M. Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases. Am J Kidney Dis. 1997;29:829-842.

(88.) Kamar N, Izopet J, Alric L, Guilbeaud-Frugier C, Rostaing L. Hepatitis C virus-related kidney disease: an overview. Clin Nephrol. 2008;69:149-160.

(89.) Da'as N, Polliack A, Cohen Y, et al. Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients. Eur J Haematol. 2001;67:158-164.

(90.) Heaton JM, Menzin MA, Carney DN. Extrarenal malignancy and the nephrotic syndrome. J Clin Pathol. 1975;28:944-946.

(91.) Usalan C, Emri S. Membranoproliferative glomerulonephritis associated with small cell lung carcinoma. Int Urol Nephrol. 1998;30:209-213.

(92.) Enriquez R, Sirvent AE, Cabezuelo JB, Perez-Ramos M, Amoros F, Reyes A. Membranoproliferative glomerulonephritis and gastric adenocarcinoma. Nephrol Dial Transplant. 1999;14:242-243.

(93.) Pascal RR, Finney RP, Rifkin SI, Kahana L. Glomerulonephritis and virus-like particles associated with prostatic cancer. Hum Pathol. 1980;11:391-399.

(94.) Reshi AR, Mir SA, Gangoo AA, Shah S, Banday K. Nephrotic syndrome associated with transitional cell carcinoma of urinary bladder. Scand J Urol Nephrol. 1997;31:295-296.

(95.) Tydings A, Weiss RR, Lin JH, Bennett J, Tejani N. Renal-cell carcinoma and mesangiocapillary glomerulonephritis presenting as severe pre-eclampsia. NY State J Med. 1978;78:1950-1954.

(96.) Ahmed M, Solangi K, Abbi R, Adler S. Nephrotic syndrome, renal failure, and renal malignancy: an unusual tumor-associated glomerulonephritis. J Am Soc Nephrol. 1997;8:848-852.

(97.) Thorner P, McGraw M, Weitzman S, Balfe JW, Klein M, Baumal R. Wilms' tumor and glomerular disease. Occurrence with features of membranoproliferative glomerulonephritis and secondary focal, segmental glomerulosclerosis. Arch Pathol Lab Med. 1984;108:141-146.

(98.) Sethi S, Sahani M, Oei LS, Rao R. Crescentic glomerulonephritis and dense deposit disease in a woman with breast carcinoma on immunosuppressive chemotherapy. Am J Kidney Dis. 2004;44:e33-e7.

(99.) Dussol B, Brunet P, Vacher-Coponat H, Bouabdallah R, Chetaille P, Berland Y. Crescentic glomerulonephritis with antineutrophil cytoplasmic antibodies associated with chronic lymphocytic leukaemia. Nephrol Dial Transplant. 1997;12: 785-786.

(100.) Pamuk GE, Uyanik MS, Demir M, Tekgunduz E, Turgut B, Soy M. Systemic antineutrophil cytoplasmic antibody vasculitis in a patient with chronic lymphocytic leukemia: quite a rare diagnosis. Leuk Res. 2007;31:1149-1151.

(101.) Hruby Z, Bronowicz A, Rabczynski J, Kopec W, Szewczyk Z. A case of severe anti-neutrophil cytoplasmic antibody (ANCA)-positive crescentic glomerulonephritis and asymptomatic gastric cancer. Int Urol Nephrol. 1994;26:579-586.

(102.) Baschinsky DY, Baker PB, Niemann TH, Wilmer WA. Pauci-immune ANCA-positive crescentic glomerulonephritis associated with metastatic adenocarcinoma of the lung. Am J Kidney Dis. 2000;36:E24.

(103.) Edgar JD, Rooney DP, McNamee P, McNeill TA. An association between ANCA positive renal disease and malignancy. Clin Nephrol. 1993;40:22-25.

(104.) von Vietinghoff S, Schneider W, Luft FC, Kettritz R. Crescentic glomerulonephritis and malignancy--guilty or guilt by association? Nephrol Dial Transplant. 2006;21:3324-3326.

(105.) Karim MY, Frankel A, Paradinas FJ, Moss J. Anti-neutrophil cytoplasmic antibody-positive crescentic nephritis occurring together with renal cell carcinoma. Nephron. 2000;85:368-370.

(106.) Whitworth JA, Morel-Maroger L, Mignon F, Richet G. The significance of extracapillary proliferation. Proc Eur Dial Transplant Assoc. 1975;11:522-525.

(107.) Tatsis E, Reinhold-Keller E, Steindorf K, Feller AC, Gross WL. Wegener's granulomatosis associated with renal cell carcinoma. Arthritis Rheum. 1999;42: 751-756.

(108.) Villa-Forte A, Hoffman GS. Wegener's granulomatosis presenting with a renal mass. J Rheumatol. 1999;26:457-458.

(109.) Norris JH, Leeds J, Jeffrey RF. P-ANCA positive renal vasculitis in association with renal cell carcinoma and prolonged hydralazine therapy. Ren Fail. 2003;25:311-314.

(110.) Lloyd M, deVerteuil J, Andrews PA. Renal vasculitis associated with renal cell carcinoma. J R Soc Med. 2002;95:305-306.

(111.) Parker MG, Atkins MB, Ucci AA, Levey AS. Rapidly progressive glomerulonephritis after immunotherapy for cancer. J Am Soc Nephrol. 1995;5:1740-1744.

(112.) Kai H, Yamagata K, Usui J, et al. Crescentic glomerulonephritis associated with renal cell carcinoma after cancer immunotherapy. J Nephrol. 2005;18:436-441.

(113.) Feriozzi S, Giannakakis K, Ranalli TV, Pofi E, Gomes V, Ancarani E. Renal oncocytoma associated with necrotizing glomerulonephritis. Ren Fail. 2006;28: 181-183.

(114.) D'Agati VD, Jennette JC, Silva FG. Non-Neoplastic Kidney Diseases. Silver Spring, MD: ARP Press; 2005:394.

(115.) Roussou M, Dimopoulos SK, Dimopoulos MA, Anastasiou-Nana MI. Wegener's granulomatosis presenting as a renal mass. Urology. 2008;71:547 e1-e2.

(116.) Vandergheynst F, Van Gansbeke D, Cogan E. Wegener's granulomatosis masquerading as a renal cancer: a case report and review of the literature. Clin Exp Rheumatol. 2006;24:584-586.

(117.) Hatakeyama S, Kawano M, Konosita T, et al. A case of renal cell carcinoma associated with rapidly progressive glomerulonephritis. Nippon Jinzo Gak kai Shi. 1990;32:1125-1132.

(118.) Susman BR, Levin FC, Barland P, Fromowitz F. Vasculitis; associated with renal oncocytoma. N Y State J Med. 1981;81:1501-1503.

(119.) Hoag GN. Renal cell carcinoma and vasculitis: report of two cases. J Surg Oncol. 1987;35:35-38.

(120.) Haas M, Spargo BH, Coventry S. Increasing incidence offocal-segmental glomerulosclerosis among adult nephropathies: a 20-year renal biopsy study. Am J Kidney Dis. 1995;26:740-750.

(121.) Ejaz AA, Geiger XJ, Wasiluk A. Focal segmental glomerulosclerosis in kidney resected for renal cell carcinoma. Int Urol Nephrol. 2005;37:345-349.

(122.) D'Agati VD, Fogo AB, Bruijn JA, Jennette JC. Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis. 2004; 43:368-382.

(123.) D'Agati VD. The spectrum of focal segmental glomerulosclerosis: new insights. Curr Opin Nephrol Hypertens. 2008;17:271-281.

(124.) Forland M, Bannayan GA. Minimal-change lesion nephrotic syndrome with renal oncocytoma. Am J Med. 1983;75:715-720.

(125.) Auguet T, Lorenzo A, Colomer E, et al. Recovery of minimal change nephrotic syndrome and acute renal failure in a patient with renal cell carcinoma. Am J Nephrol. 1998;18:433-435.

(126.) Martinez-Vea A, Panisello JM, Garcia C, et al. Minimal-change glomerulopathy and carcinoma. Report of two cases and review of the literature. Am J Nephrol. 1993;13:69-72.

(127.) Beisland C, Talleraas O, Bakke A, Norstein J. Multiple primary malignancies in patients with renal cell carcinoma: a national population-based cohort study. BJU Int. 2006;97:698-702.

(128.) Rabbani F, Reuter VE, Katz J, Russo P. Second primary malignancies associated with renal cell carcinoma: influence of histologic type. Urology. 2000; 56:399-403.

(129.) Kunthur A, Wiernik PH, Dutcher JP. Renal parenchymal tumors and lymphoma in the samepatient: case series and review of the literature. Am J Hematol. 2006;81:271-280.

(130.) Kiely JM, Wagoner RD, Holley KE. Renal complications of lymphoma. Ann Intern Med. 1969;71:1159-1175.

(131.) Sullu Y, Donmez G, Kandemir B, Gun S. Renal cell carcinoma with non-Hodgkin's lymphoma infiltration: a case report. Pathol Res Pract. 2007;203:625-627.

(132.) Nishikubo CY, Kunkel LA, Figlin R, et al. An association between renal cell carcinoma and lymphoid malignancies. A case series of eight patients. Cancer. 1996;78:2421-2426.

(133.) Anderson CM, Pusztai L, Palmer JL, Cabanillas F, Ellerhorst JA. Coincident renal cell carcinoma and non-Hodgkin's lymphoma: the M. D. Anderson experience and review of the literature. J Urol. 1998;159:714-717.

(134.) Wang BY, Strauchen JA, Rabinowitz D, Tillem SM, Unger PD. Renal cell carcinoma with intravascular lymphomatosis: a case report of unusual collision tumors with reviewofthe literature. Arch Pathol Lab Med. 2001;125:1239-1241.

(135.) Jimenez VH. Coexistence between renal cell cancer and Hodgkin's lymphoma: a rare coincidence. BMC Urol. 2006;6:10.

(136.) Radin DR, Chandrasoma P. Coexistent xanthogranulomatous pyelonephritis and renal cell carcinoma. J Comput Tomogr. 1987;11:294-6.

(137.) Argani P, Olgac S, Tickoo SK, et al. Xp11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum. Am J Surg Pathol. 2007;31:1149-1160.

(138.) Papadopoulos I, Wirth B, Wand H. Xanthogranulomatous pyelonephritis associated with renal cell carcinoma. Report on two cases and review of the literature. Eur Urol. 1990;18:74-76.

(139.) Val-Bernal JF, Castro F. Xanthogranulomatous pyelonephritis associated with transitional cell carcinoma of the renal pelvis. Urol Int. 1996;57:240-245.

(140.) Bottalico T, Parks S, Zaslau S, Tarry WF. Pediatric xanthogranulomatous pyelonephritis masquerading as complex renal mass. Urology. 2007;70:372.e11-e12.

(141.) Mittal BV, Pendse S, Rennke HG, Singh AK. Hematuria in a patient with class IV lupus nephritis. Kidney Int. 2006;70:1182-1186.

(142.) Rosenstock JL, Markowitz GS, Valeri AM, Sacchi G, Appel GB, D'Agati VD. Fibrillary and immunotactoid glomerulonephritis: distinct entities with different clinical and pathologic features. Kidney Int. 2003;63:1450-1461.

(143.) Ng CS, Gill IS. Impact of renal cryoablation on urine composition. Urology. 2002;59:831-834.

(144.) Stefanovic V, Radovanovic Z. Balkan endemic nephropathy and associated urothelial cancer. Nat Clin Pract Urol. 2008;5:105-112.

(145.) Chen CY, Liao YM, Tsai WM, Kuo HC. Upper urinary tract urothelial carcinoma in eastern Taiwan: high proportion among all urothelial carcinomas and correlation with chronic kidney disease. J Formos Med Assoc. 2007;106:992-998.

(146.) Handa SP, Tewari HD. Urinary tract carcinoma in patients with analgesic nephropathy. Nephron. 1981;28:62-64.

(147.) Moshakis V, Hooper AA. Analgesic nephropathy and transitional cell carcinoma. Postgrad Med J. 1978;54:285-286.

(148.) Lornoy W, Becaus S, de Vleeschouwer M, et al. Renal cell carcinoma, a new complication of analgesic nephropathy. Lancet. 1986;1:1271-1272.

(149.) Nadasdy T, Laszik Z, Blick KE, Johnson DL, Silva FG. Tubular atrophy in the end-stage kidney: a lectin and immunohistochemical study. Hum Pathol. 1994;25:22-28.

(150.) Tickoo SK, dePeralta-Venturina MN, Harik LR, et al. Spectrum of epithelial neoplasms in end-stage renal disease: an experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am J Surg Pathol. 2006;30:141-153.

Kammi J. Henriksen, MD; Shane M. Meehan, MB, BCh; Anthony Chang, MD

Accepted for publication August 27, 2008.

From the Department of Pathology, University of Chicago Medical Center, Chicago, Illinois.

Presented in part at the Current Issues in Diagnostic Pathology conference, University of Chicago, Chicago, Illinois, November 2008.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Anthony Chang, MD, Department of Pathology, University of Chicago Medical Center, MC6101, 5841 S Maryland Ave, Chicago, IL 60637 (e-mail:
COPYRIGHT 2009 College of American Pathologists
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2009 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Henriksen, Kammi J.; Meehan, Shane M.; Chang, Anthony
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Geographic Code:1USA
Date:Jul 1, 2009
Previous Article:Update in surgical pathology.
Next Article:Recent developments in the pathology of renal tumors: morphology and molecular characteristics of select entities.

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters |