Diagnosing nonneoplastic lesions in nephrectomy specimens.
Abstract: * Context.--Nonneoplastic changes are often identified in nephrectomy specimens removed for renal neoplasms. Although they may be of prognostic or therapeutic importance, they are often overlooked. Nephrectomy is also performed for nonneoplastic lesions, the most frequent of which are urinary obstruction and end-stage renal disease, but the tissue diagnosis of these conditions and the implicated clinicopathologic correlation may not be well appreciated.

Objective.--To outline these nonneoplastic lesions with special attention to important diagnostic caveats and clinicopathologic correlations.

Data Sources.--The presented information was derived from literature, personal experience, and review of case materials at the authors' institutions.

Results.--Nonneoplastic lesions are seen in most (90%) nephrectomy specimens removed for renal neoplasms. Although these lesions span the spectrum of "medical" kidney diseases, the most frequent of them are hypertensive nephrosclerosis and diabetic nephropathy. Recognition of these diseases is important because they are often first diagnosed and later confirmed clinically. Furthermore, the severity of these lesions may predicate both short- and long-term renal function and thus help guide treatment. Among conditions that necessitate nephrectomy, advanced urinary obstruction, end-stage renal disease, and end-stage renal disease with acquired cystic changes are probably the most frequent. These conditions have characteristic morphologic features, but they may be associated with superimposing lesions previously not well described. These superimposing lesions may create diagnostic confusion; yet, some of them are the reason for nephrectomy. Thus, acute bacterial infection, urine polyp, granulomatous pyelitis, papillary necrosis, massive bleeding, and renal dysplasia can develop against the background of obstructive nephropathy. Renal neoplasms may develop from the background of end-stage renal disease without cystic changes. A renal neoplasm or massive bleeding with or without neoplasm is usually the reason for nephrectomy in kidney with acquired cystic kidney diseases. Thus, while nonneoplastic changes are frequent in nephrectomy specimens, they are often unrecognized. Awareness of these conditions and a familiarity with their diagnostic features as well as the implicated clinicopathologic correlation should help obviate this diagnostic problem.
Article Type: Report
Subject: Kidney cancer (Care and treatment)
Kidney cancer (Prognosis)
Kidney cancer (Diagnosis)
Nephrectomy (Usage)
Nephrectomy (Patient outcomes)
Authors: Truong, Luan D.
Shen, Steven S.
Park, Moon-Hyang
Krishnan, Bhuvaneswari
Pub Date: 02/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: Feb, 2009 Source Volume: 133 Source Issue: 2
Accession Number: 230151955
Full Text: Partial or total nephrectomy is most often performed to remove renal neoplasms. Several nonneoplastic conditions that are clinically unsuspected are often identified in these specimens. For example, diabetic nephropathy or hypertensive renal injury of a significant extent may be recognized first in these specimens. Furthermore, specific glomerular diseases may not come to clinical attention prior to nephrectomy. Although these conditions may be of prognostic or therapeutic importance, they are often overlooked. Less often, nephrectomy is also performed for nonneoplastic lesions, as listed in Table 1.

This review outlines these nonneoplastic changes. Rather than being comprehensive, it will focus on (1) nonneoplastic renal diseases in kidneys removed for tumors, (2) obstructive nephropathy and related conditions, and (3) nephrectomy in the context of end-stage renal disease, with special attention to important diagnostic caveats and clinicopathologic correlations. These conditions are selected not only because they are rather frequent and may be of clinical importance, but also because there are pertinent clinicopathologic findings that were previously underemphasized.

NONNEOPLASTIC RENAL DISEASES IN KIDNEY REMOVED FOR TUMOR

General Considerations

Nonneoplastic changes in these specimens are usually of 3 types. (1-7) First, there are changes in the renal parenchyma adjacent to the tumor without any significant changes elsewhere. These changes include tubular atrophy and interstitial fibrosis/mild chronic inflammation, with or without glomerulosclerosis. These changes, which are noted in most renal tumors and are probably of ischemic nature due to local mass effects, are of no clinical significance. In rare cases a peculiar peritumoral change composed of smooth muscle bundles and blood vessels of capillary type termed angioleiomyoma-like proliferation is noted. This has no clinical significance and is perhaps related to the localized cytokine effects of the tumor cells.8 Second, large renal cell neoplasms, especially those which are centered in renal medulla or urothelial carcinoma, may be associated with chronic obstructive nephropathy, as described in detail below. Third, the changes are present throughout the kidney. This type of lesion is frequent (seen in about 90% of specimens) and may be of clinical significance, but is often missed. (1,2) The lesions are detailed below.

Pathologic Changes

A large spectrum of changes is noted (Table 2), the most frequent of which are arterial nephrosclerosis without (29%) or with (22%) renal tissue scarring, and diabetic nephropathy (23%). (1,2)

The arterial nephrosclerosis is characterized by vascular changes, including hyaninosis involving predominantly arterioles (Figure 1, C) and intimal fibrous thickening involving arteries regardless of size (Figure 1, B). These vascular changes probably represent aging changes, reflecting the older age of those with renal neoplasms, (9) or are due to hypertension often seen in this group of patients. (1,9) The renal parenchyma may be normal or display chronic ischemic injury of variable severity. This is characterized by focal global glomerulosclerosis, patchy tubular atrophy, interstitial fibrosis, and mild mononuclear inflammatory cell infiltrates. These changes are most pronounced in the subcapsular areas or in the vicinity of the arterial blood vessels with fibrointimal thickening (Figure 1, A).

[FIGURE 1 OMITTED]

The diabetic changes may be mild (mild global or segmental mesangial sclerosis and hypercellularity; Figure 1, C) or marked (severe mesangial changes, including Kimmelstiel-Wilson mesangial nodules, and thickened glomerular capillaries without endocapillary cell proliferation; Figure 1, C, inset). Vascular changes, as in the case of arterial nephrosclerosis described above, and chronic tubulointerstitial changes are also frequent, which may be due to diabetes itself, the frequently associated hypertension, or both.

Other diseases are seen less often, but their morphology is not different from that in renal biopsy specimens (Table 2).

The spectrum of these renal parenchymal changes is similar in partial and total nephrectomy specimens. (1,2) There seems to be an interesting association of some of these lesions to the histologic types of renal neoplasm, regardless of tumor size. Thus, Bijol et al (1) noted that diabetic changes are more frequent in kidneys with clear cell renal cell carcinoma (RCC; 30%) than those with other tumor types (11%), vascular/ischemic changes are most frequent in kidneys with urothelial carcinoma (55%), and normal renal parenchyma is most often seen in kidneys with chromophobe RCC or oncocytoma (83%), the 2 types of renal neoplasm well known for their indolent behavior.

Clinicopathologic Correlations

The explanation for the high incidence of renal parenchymal changes in tumor nephrectomy specimens is not obvious. This may just reflect the higher incidence of diabetes or hypertension in the elderly population, the preference age group for renal neoplasms. (1,2,9) However, a pathogenetic association between renal neoplasms and the parenchymal lesions is also possible. Thus, the incidence of diabetic changes in tumor nephrectomy specimens (24%) is significantly higher than that in the general population, even in those older than 65 years (18%). (1)

Recognizing the above conditions in tumor nephrectomy specimens can be very significant. (1-7) In many cases these conditions are first diagnosed, and later they are confirmed clinically. (1,2) Furthermore, Bijol et al (1) have documented that the renal function in patients with unequivocal diabetic nephropathy or marked vascular/ischemic renal changes is progressively deteriorated as early as 3 to 6 months after nephrectomy, but shows only minor changes in those with milder or no renal parenchymal lesions. The therapeutic and prognostic implications of these observations are obvious. Hypertension, smoking, diabetes, obesity, and aging are risk factors for chronic renal insufficiency. (9-12) They also are risk factors for renal neoplasms. (9,12) Therefore, nephrectomy for tumor leading to nephronic loss is expected to further erode the renal reserve of those whose renal function was already impaired. (6,7,10,11) Thus, an early diagnosis and prompt treatment of the above associated conditions may prevent progressive renal failure.

In spite of their high incidence and clinical significance, these lesions often are missed. In this aspect it is noted in a recent survey that only 29% of pathology residency programs offer formal training in medical renal pathology. (2) To facilitate the diagnosis, it is recommended that tissue samples are taken from the parenchyma away from the tumor mass because the areas adjacent to the tumor almost always show nonspecific chronic changes, and routine histochemical staining, including periodic acid-Schiff and Masson trichrome stains, should be performed. (1,2) Awareness of these associated conditions and, perhaps, renal pathology consultation should lead to a correct diagnosis in most cases. Immunofluorescent and/or electron microscopy (EM) studies are rarely needed, but they can be effectively performed on routinely processed tissue samples, obviating the need for tissue being snap frozen for immunofluorescence or fixed in specialized electron microscopy fixatives. (13)

OBSTRUCTIVE NEPHROPATHY, REFLUX NEPHROPATHY, HYDRONEPHROSIS, AND CHRONIC PYELONEPHRITIS

General Considerations

Kidney removed for one of these distinct but related conditions is the most frequent type of nephrectomy specimen for nonneoplastic renal diseases in both adults and children.

Definition of these conditions facilitates their diagnosis. (14,15) Obstructive nephropathy represents renal changes due to urinary obstruction, regardless of cause, anywhere between the ureteropelvic junction to the urethra. Reflux nephropathy, which also is called chronic nonobstructive pyelonephritis, is defined as reflux of urine from the urinary bladder through an incompetent vesicoureteral junction and into the ureter and pyelocaliceal system and, eventually, into the renal parenchyma, without mechanical obstruction of the urine outflow tract. Hydronephrosis is defined as dilatation of the pyelocaliceal system, regardless of whether this is due to mechanical obstruction of urine or urine reflux without mechanical obstruction. Chronic pyelonephritis denotes chronic inflammation and the associated tissue injury involving not only the renal parenchyma but also the pyelocaliceal system. This is almost always associated with urinary obstruction or reflux. This term also traditionally implies bacterial infection in the pathogenesis of the tissue changes, although there is not universal agreement on this point.

Most of the time, treatment for these conditions does not involve nephrectomy. (14,15) Nephrectomy is usually indicated for advanced disease causing irreversible loss of renal function (usually defined as a contribution to global renal function of less than 10% or a glomerular filtration rate of less than 10 mL/min), intractable pain, recalcitrant hypertension, repeated local/systemic infection, or rarely, for bleeding leading to large hematoma. (14-17) The long-term outcome of the patient or of the remaining kidney after nephrectomy, however, has not been systematically studied.

As detailed further below, the nephrectomy specimens with these conditions show a similar spectrum of renal changes. Against this common background lesion there are also additional changes suggestive of individual conditions, but these latter changes are not constant. These observations reflect the same spectrum of pathogenetic elements for these conditions, including the effects of urinary obstruction (ischemic injury, chemokine-mediated inflammatory cell recruitment, and interstitial fibrosis), direct parenchymal bacterial infection-induced injury, and reflux of urine of variable severity (from the bladder to different levels of the ureter, and then into the renal parenchyma). Some of these factors are of primary nature and are more pathogenetically important than others in the initial phases of a specific condition. However, in each of these conditions, the other factors will subsequently add to the injury. For example, although "pure" urinary obstruction can cause renal injury, superimposed bacterial infection is almost always present in this situation. Urinary obstruction may be a primary cause of renal injury in renal lithiasis, but subsequent urinary tract infection often occurs and causes further renal injury. Urine reflux is primarily responsible for the renal injury in reflux nephropathy, but an element of urinary obstruction with hydronephrosis, which is frequent in the late phases of reflux nephropathy, aggravates the injury. (14,15)

Gross Features

The kidney with obstructive nephropathy shows diffuse thinning of the renal parenchyma of variable degrees (sometimes to a few millimeters), loss of corticomedullary junction landmark, blunting or loss of renal papillae, and dilatation of the pyelocaliceal system (hydronephrosis) and thickening of its wall (Figure 2, A). Rarely, there are also changes suggestive of complications, including papillary necrosis, parenchymal abscesses, or large hematoma. The causes of urinary obstruction may be obvious (eg, tumor or stones) or suspected (eg, ureteropelvic obstruction characterized by an abrupt transition between a dilated renal pelvis and a normal or even atrophic ureter; Figure 2, B), but they often cannot be determined from gross examination.

The kidney with reflux nephropathy has a broad spectrum of changes. (14,15) At one end it is similar to severe obstructive uropathy. In these cases one of the most characteristic changes is that the ureter is not only markedly dilated but also tortuous, reflecting a severe degree of urinary reflux. In milder cases only a portion of the renal parenchyma is scarred, and only the corresponding portion of the pyelocaliceal system is dilated and thickened, with the rest of the kidney being normal or even showing some compensatory hypertrophy (Figure 3). The affected area is usually the upper pole, where the renal pyramids are shaped in a way that facilitates intrarenal reflux. The diagnosis may be missed in these cases at both gross and microscopic levels. This is due to the observation that the affected area, including the dilated portion of the pyelocaliceal system, may be focal and collapsed postoperatively, and thus masked by the adjacent normal kidney tissue. This leads to failure to recognize the lesion grossly and to sample it for microscopic examination.

Microscopic Features

The renal parenchymal changes common to all of the above conditions are marked chronic tubulointerstitial nephritis, with disproportionately milder glomerular or vascular changes.

The tubulointerstitial changes include tubular atrophy, thickened tubular basement membrane, tubular hyaline casts, interstitial fibrosis, and interstitial mononuclear inflammatory cell infiltrates (Figure 2, C). Tamm-Horsfall protein with characteristic morphology (glassy pale in hematoxylineosin, and strongly periodic acid-Schiff positive) is often seen either in tubular lumen or interstitium (Figure 2, D). The glomeruli, which appear crowded as the result of the tubulointerstitial tissue loss, are either normal or show compensatory hypertrophy, chronic ischemic, and/or "obstructive" changes (small size, mild collapse, wrinkling of glomerular capillaries, and enlarged urinary spaces; Figure 2, E and F). The blood vessels are either normal in early course or display marked fibrointimal thickening (Figure 2, E), reflecting either intrarenal or systemic hypertension rather than obstructive effects, and perhaps accounting for some of the glomerular changes. (15,18) The pyelocaliceal changes are an integral element of the lesion. They include urothelial reactive atypia, fibrosis, and chronic inflammation of the lamina propia, and often marked thickening of the muscularis (Figure 2, G).

Against this common background, some changes may suggest a specific condition. Thus, diffuse involvement favors obstructive uropathy. Patchy renal parenchymal affliction characterized by severe changes next to normal areas, or marked dilatation and tortuosity of the ureter indicates reflux nephropathy. The diagnosis of chronic pyelonephritis is suggested in the presence of "significant" chronic inflammation of both renal parenchyma and the pyeolocaliceal system (Figure 2, E). This diagnosis, as mentioned above, may signify superimposing bacterial infection; nevertheless, bacteria are virtually never seen by special stains, and cultures are often negative, leading to the experimentally supported idea that sterile urine reflux or urinary obstruction can cause tissue injury, including marked chronic inflammation. (14,15)

Associated Conditions

Some rare conditions are seen in nephrectomy specimens for urinary obstruction/reflux nephropathy. They include acute bacterial infection, urine polyp, granulomatous pyelitis, papillary necrosis, hematoma, and dysplastic changes. Some of them are described herein because they have characteristic morphology or may not be described in standard textbooks.

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Superimposed acute bacterial infection is usually due to ascending infection. It is characterized by neutrophil infiltration against the background of chronic obstructive nephropathy, which forms gross or microscopic abscesses involving the tubules, interstitium, and pyelocaliceal system, but usually spares blood vessels and glomeruli (Figure 4). These findings should prompt culture studies and/ or bacterial stains, which are often positive. This condition is different from hematogenous bacterial infection, which usually develops in intact kidney and for which medical treatment rather than nephrectomy is indicated.

Urine polyp is characterized by accumulation of Tamm-Horsfall protein, a protein secreted exclusively by the distal portion of the nephron, forming a mass in the lumen of intrarenal lymphatic or venous channels. It has characteristic and diagnostic morphology (glassy and faintly eosinophilic in hematoxylin-eosin; fibrillary and strongly positive by periodic acid-Schiff; light blue in trichrome; Figure 5). As mentioned above, microscopic tubular or interstitial accumulation of this protein is rather frequent in obstructive nephropathy; however, urinary obstruction can rarely create a connection between tubular lumen or renal pelvic lumen and the adjacent vascular channels, accounting for the formation of urine polyp. (19,20)

[FIGURE 4 OMITTED]

Granulomatous pyelitis is characterized by granulomatous inflammation limited to the pyelocaliceal wall and without involvement of the renal parenchyma. The granulomatous inflammation characteristically appears as palisading histiocytes/macrophages along the pyolecaliceal wall, associated with loss of urothelium (Figure 6). This condition has been reported in about 4% of nephrectomy specimens for urinary obstruction. (21) This condition is probably not of infectious etiology because organisms have not been detected by cultures and/or special stains. Most cases are associated with marked pyelocaliceal inflammation, tissue necrosis, Tamm-Horsfall protein accumulation, calcific debris, and stones, suggesting a pathogenetic link. (21)

[FIGURE 5 OMITTED]

Dysplastic changes are defined as altered metanephric differentiation during embryogenesis, leading to abnormal kidney. They are characterized by renal tubular cysts lined by a single layer of cuboidal, occasionally ciliated cells with hyperchromatic nuclei and scanty cytoplasm reminiscent of the primitive renal tubules normally seen during renal development, as well as immature glomeruli or renal tubules separated by an immature mesenchyme that tends to form hypercellular concentric rings with frequent myofibroblastic differentiation around the cysts or primitive tubules. The mesenchyme also shows abnormal differentiation in the form of mature cartilage islands, or rarely, mature adipose tissue. Although renal dysplasia can be due to numerous causes, urinary obstruction during renal embryogenesis is probably the most frequent cause. (22,23) Thus, renal dysplasia is seen only in urinary obstruction in children but not in adults, and in this context it is restricted to the obstructed areas of the kidney. Other changes directly related to urinary obstruction can also be seen in this context but may be inconspicuous.

[FIGURE 6 OMITTED]

We have seen a few cases of acute and severe bleeding complicating obstructive nephropathy although there are no published reports of this complication. This leads to large renal hematomas, necessitating nephrectomy. The hematoma is noted against the background of severe obstructive changes, including tortuous small arteries with marked fibrointimal thickening, which may be the source of bleeding (Figure 7). The reason for bleeding is not clear in these cases.

[FIGURE 7 OMITTED]

NEPHRECTOMY IN THE CONTEXT OF END-STAGE RENAL DISEASE

General Considerations

Nephrectomy is performed increasingly in the context of end-stage renal disease (ESRD). Kidneys with ESRD show characteristic changes (see below). These kidneys can also develop acquired cystic kidney disease (ACKD), characterized by cystic dilatation of renal tubules, with an increasing incidence in parallel with the duration of dialysis (87% after 9 years). End-stage kidney disease with or without ACKD is usually asymptomatic and does not require any treatment, but it is usually followed by serial imaging studies. However, kidneys with these conditions can give rise to 2 distinct but related major complications; that is, severe bleeding and renal neoplasms, for which nephrectomy may be indicated. (24-28) Other less frequent indications for this type of nephrectomy include intractable hypertension, pain, and repeated infections. Recognizing these indications should aid the gross and microscopic examination of the nephrectomy specimens. It should be noted that these lesions can be seen in the native kidney with ESRD even after successful renal transplantation. (29)

Bleeding is seen in up to 17% of kidneys with ACKD. (27,28) This may derive from unsupported blood vessels within the flimsy cyst walls and is promoted by uremia-associated coagulation defects or dialysis-related heparinization (about 70% of cases). Alternatively, bleeding may derive from renal tumors (about 30% of cases) and, indeed, is the frequent initial presentation of these tumors. (28) The bleeding may be massive and occur selectively in intrapelvic, intraparenchymal, subcapsular, or retroperitoneal locations, causing gross hematuria, anemia, shock, renal mass, flank pain, and renal colic. (24,26,28)

Patients with ESRD are known to develop renal neoplasms, including renal cell carcinoma, at a frequency 8to 10-fold higher than that of the general population. These renal neoplasms can develop from the background of ACKD and probably derive from cysts with dysplastic lining cells. (24,30-32) Alternatively, they can be seen against the background of ESRD changes only, without cystic changes. (29-31) Most cases (86%) are asymptomatic, and the symptomatic neoplasms are related mostly to bleeding complications. Indeed, many tumors manifest exclusively with persistent hematuria and are undetectable by any available imaging techniques. (24,28)

Nephrectomy is recommended for a tumor measuring more than 3 cm or for those of smaller sizes that are associated with persistent hematuria or rapid growth, because on nephrectomy many of the latter tumors turn out to be unequivocal RCCs. (24,26) In many cases, in spite of sophisticated imaging techniques, preoperative differentiation between cysts with infection or bleeding and tumors is not possible. The complex and variegated renal changes may preclude assessment of tumor size, a main determinant of benign versus malignant. Empirical nephrectomy is usually performed for these cases. (24,26) The long-term outcome of the patient or of the remaining kidney after nephrectomy, however, has not been studied systematically.

This type of nephrectomy specimen is expected to become more numerous. This is because the number of ESRD patients on dialysis is increasing, these patients survive longer, and the incidence of ACKD increases with the duration of dialysis to reach virtually 100% after 10 years, all leading to a concomitant increase in the incidence of the associated renal neoplasms. (25)

Pathologic Considerations

The spectrum of changes in these nephrectomy specimens includes ESRD changes, ACKD changes, and renal neoplasms, but they are seen in various combinations in each specimen. Although the ESRD and ACKD changes involve both kidneys, usually only one kidney is removed, because renal neoplasm is the main reason for nephrectomy. The kidney thus often harbors tumors against the background of ESRD changes. As mentioned above, because renal neoplasm in the context of ESRD may develop de novo or through tubular cysts, these nephrectomy specimens may or may not show additional ACKD changes. Mass lesions, including hematoma and cysts with such complications as intracystic bleeding or infection/abscess, may simulate neoplasm, and they, rather than tumors, are found in the nephrectomy specimens. The discussion below focuses on the ESRD and ACKD changes and the related complications. Several previous excellent reviews are devoted to the ESRD-associated renal neoplasms. (30-32)

ESRD Changes

Grossly, the kidneys with ESRD only are small (weight, 4-120 g; Figure 8, A). These kidneys remain small even in the presence of a tumor, perhaps reflecting early detection through serial imaging and timely removal when the tumor is still small. These kidneys retain a reniform appearance with a finely granular surface. The combined cortical and medullary thickness is markedly decreased, with enlargement of the renal sinus, but the pyelocaliceal system is normal. The corticomedullary junction is blurred.

Microscopically, most glomeruli are globally sclerotic with or without hyalinosis, and they do not reveal the primary disease. However, in many cases the nature of the primary glomerular disease can still be recognized in glomeruli with less advanced changes. (33,34) Some examples include chronic ischemic/hypertensive changes (reduced glomerular size, subcapsular fibrosis starting from the vascular pole with intact capsule of Bowman, and wrinkling and collapse of glomerular capillaries; Figure 8, C), diabetic glomerulosclerosis (enlarged glomerular size, faint nodular or diffuse mesangial enlargement, and thickening of the glomerular capillaries; Figure 8, D), or glomerulonephritis (normal glomerular size, glomerular capsular adhesion, pseudotubular formation, fibrous crescent, or even features of some specific glomerulonephritis type, ie, membranous or membranoproliferative glomerulonephritis; Figure 8, E and F). In many cases, against the background of global sclerosis involving most glomeruli, a rare normal glomerulus is still present, surprisingly. Other rare but distinctive changes, albeit of no diagnostic significance, are present; for example, embryonal hyperplasia of Bowman capsular epithelium. Electron microscopy and immunofluorescence may be helpful in evaluating the original disease, but these are not recommended for routine evaluation. (33,34)

[FIGURE 8 OMITTED]

The tubulointerstitial compartment shows diffuse chronic changes. (33) There is tubular atrophy, dilatation, thickened tubular basement membrane, and hyaline casts (Figure 8, B), but acute changes, such as necrosis, cellular disruption, or apoptosis, are not obvious. In most cases a few tubular cross sections without changes or even with compensatory hypertrophy are noted. There is diffuse interstitial fibrosis and inflammation involving both cortex and medulla. The interstitial inflammatory cell infiltrates, which include predominantly lymphocytes and monocytes, with fewer plasma cells, can be marked, but this does not imply infection. However, marked neutrophilic infiltration suggests superinfection, for which further special stains to document organisms should be initiated. The pyelocaliceal system should not show significant changes; however, if ESRD is due to chronic pyelonephritis, characteristic changes of the pyelocaliceal system, as described above, should be seen. One of the most characteristic tubulointerstitial changes seen in most cases is calcium oxalate crystal deposition, which can be extensive. These crystals can be seen in tubular lumen, tubular cells, or interstitium (Figure 8, B). Oxalate, which is normally excreted by the kidney, could not be removed effectively by dialysis in the context of ESRD, leading to high serum levels and tissue deposition. In contrast with the case of ACKD, interstitial hemorrhage is not seen.

The arterial blood vessels show characteristic changes, such as by marked concentric fibrous or fibromucoid intimal thickening, intact internal elastic lamina, and mild medial hyperplasia, involving blood vessels of all sizes (Figure 8, B). These changes are most probably related to prolonged dialysis, and are thus seen in virtually every case, regardless of the nature of the primary renal diseases or the blood pressure levels.

[FIGURE 9 OMITTED]

Changes of ACKD

Grossly, cystic changes indicate the development of ACKD from the background of ESRD. The kidneys with ACKD are usually small (weight: range, 5-458 g; mean, 99 g), with about 87% of them weighing less than normal (about 150 g). The weight reduction, in spite of the presence of cysts and their content, is due to the fact that cysts develop not from a normal kidney but from a severely atrophic kidney associated with ESRD. Indeed, a serial computed tomographic scan study showed that the size of kidneys in dialysis patients decreased during the first 3 years of dialysis, and they subsequently increased in conjunction with cyst formation. (35) Exceptionally, a kidney with ACKD may reach a large size, look similar to a fully developed autosomal dominant polycystic kidney, and weigh as much as 1250 g, a value highly unusual for ACKD but average for kidneys with autosomal dominant polycystic kidney disease. Heavier weights, however, usually imply bleeding complications or neoplastic transformations (see below). (24,26,27,36)

The kidney with ACKD is composed of cysts with a size range from microscopic to about 2 cm, but about 60% of them are smaller than 0.2 cm. (36) Larger cysts, a frequent feature of autosomal polycystic kidney disease, can occur but are distinctly rare. The cut surface may display a few scattered larger cysts involving only cortex (Figure 9, A), diffuse small cysts imparting a spongy appearance to the kidney, or variably sized cysts dispersed throughout parenchyma (Figure 9, B). The highly variable extent of cystic changes among kidneys with ACKD is expected, considering the fact that the severity of cystic change is continuously progressive and is determined by several factors, including the duration of dialysis. This variation, however, raises questions concerning the degree of cystic change that establishes the diagnostic threshold for ACKD. Although the continuous progression of cystic changes in ACKD renders any reported threshold somewhat arbitrary, which indeed ranges from a few cysts to cystic changes involving 40% of the renal tissue, (37-39) the suggestion of Granthem (39) for a minimum of 5 grossly observable cysts seems to be a reasonable requirement. Such criteria would exclude cases of multiple, incidental simple cysts, the only other cystic condition that, in theory, can arise from the background of ESRD. The cysts are unilocular and contain clear, straw-colored or, less frequently, gelatinous fluid. Bleeding is a frequent finding. Bleeding, seen in about 17% of cases, may appear in the form of intact cysts with bloody or dark puttylike content representing degenerated blood, but they can be so massive that the entire nephrectomy specimen looks like a hematoma (Figure 9, C). (28,36,40) Bleeding forming a mass may simulate neoplasm by imaging, but careful gross and microscopic examination does not show tumor. However, bleeding often indicates an underlying tumor. Indeed, the following features should prompt a careful search for tumor: male sex, prolonged dialysis, heavy kidney (heavier than 150 g), and large hematomas. (24,26) Gehrig et al (28) noted that among 24 cases in which nephrectomy was performed for intractable hematuria, RCC, not visualized preoperatively, was identified in 8 cases.

Microscopically, almost all cysts derive from tubules, and they are noted against the constant background of ESRD described above. They are lined by a single layer of epithelium, which is variously composed of flat, nondescript cells, cells with abundant cytoplasm containing hyaline droplets similar to those seen in hypertrophic proximal tubules, or small cuboidal cells resembling distal tubular or collecting duct cells (Figure 9, D). Virtually every kidney with ACKD displays some cysts with atypical features of the cyst-lining cells. These include cellular atypia (enlarged, hyperchomatic nuclei with irregular contour and loss of polarity), multilayering, intracystic papillary formations, or microscopic mural nodules (Figure 9, D through F). These atypical cysts may be preneoplastic and are more frequent in cases with renal tumors. Cysts usually show secondary changes, including intracystic bleeding, and deposition of necrotic cell debris, hemosiderin, macrophages, or calcium oxalate deposition (Figure 9, D [inset], F, and G); these changes may be microscopic, may be severe and associated with destruction of the cyst epithelium, or may involve the noncystic renal tissue. In some cases, as mentioned above, these degenerative changes, especially bleeding, are extensive and create mass effect (Figure 9, G). Careful examination is needed because these "masses" may be nonneoplastic, but in about 30% of cases there is neoplasm associated with but masked by the hematomas. (28) In some cases glomerular cysts due to dilatation of the urinary space are widespread and contribute to the cystic appearance of the kidney. (33)

Specialized studies, including electron microscopy, nephron dissection, immunohistochemistry, and lectin histochemistry, suggest that cysts begin as outpouching or sacculation of intact tubular segments from all levels of the nephron and then develop into cysts through continuous proliferation of tubular cells. Indeed, ultrastructural or molecular features of normal distal or proximal tubules are recognized focally in cyst-lining cells. (24,26)

In summary, nonneoplastic changes are frequent in tumor nephrectomy specimens. Several of them are of prognostic and therapeutic importance, yet they are often missed. Awareness of these conditions and a familiarity with their diagnostic features should help obviate this potential problem.

Accepted for publication October 15, 2008.

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Luan D. Truong, MD; Steven S. Shen, MD; Moon-Hyang Park, MD, PhD; Bhuvaneswari Krishnan, MD

From the Department of Pathology, The Methodist Hospital and Research Institute, Houston, Tex (Drs Truong and Shen); the Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea (Dr Park); and the Pathology Department, Baylor College of Medicine and Veterans Affairs Hospital, Houston, Tex (Dr Krishnan).

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

Reprints: Luan D. Truong, MD, Department of Pathology, The Methodist Hospital and Research Institute, 6565 Fannin St, M227 (Main Bldg), Houston, TX 77030 (e-mail: ltruong@tmhs.org).
Table 1. Nonneoplastic Conditions in
Nephrectomy Specimens

Medical renal diseases in nephrectomy specimens removed
  for renal neoplasms
Obstructive nephropathy/reflux nephropathy
Nephrectomy specimens from patients with end-stage renal
  disease
Renal arterial stenosis
Renal inflammatory/infectious conditions
  Xanthogranulomatous pyelonephritis
  Malakoplakia
  Abscess
  Tuberculosis
Cystic renal diseases
  Polycystic kidney disease, autosomal dominant
  Polycystic kidney disease, autosomal recessive
  Dysplastic kidney
Traumatic rupture

Table 2. Nonneoplastic Changes in Nephrectomy
Specimens Removed for Renal Neoplasms *

Changes                                       Percentage

Normal                                            10
Vascular changes with normal parenchyma           29
Vascular changes with parenchymal scarring        22
Diabetic nephropathy                              23
Others                                             8
  Atheroembolism                                   2
  Acute tubulointerstitial nephritis               2.7
  BCG-related granulomatous                        0.9
    interstitial nephritis
  IgA nephropathy                                  1.8
  Collapsing glomerulopathy                        1.8
  End-stage renal disease                          1.8
  Thin glomerular basement membrane disease        1.8
  Amyloidosis                                      0.9
  Chronic thrombotic microangiopathy               4.6
  Sickle cell nephropathy                          0.4
  Focal segmental glomerulosclerosis               0.4
  Hydronephrosis                              ([dagger])

* Data are taken from Bijol et al (1) and Henriksen et al. (2) BCG
indicates Bacille Calmette-Guerin; IgA, immunoglobulin A.

([dagger]) L. D. Truong, MD, unpublished data, 2008.
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