The kidney serves many functions critical to homeostasis including blood filtration, volume control, and secretion and reabsorption of electrolytes, small molecules and proteins. This complexity of function is paralleled in an elegantly organized structure.1,2 It is one of the most anatomically complicated organs and the organ system most prone to malformations that affect ∼10% of the population.3 The kidneys are vulnerable to hematogenous assault from a variety of systemic diseases, especially hypertension and diabetes, and iatrogenic therapies or exogenous exposures. Its lower urinary output passes through multiple organs and is open to the external environment potentially leading to obstructive complications and retrograde infections.
The diagnosis of kidney disease is also complex. Many medical diseases are championed by renal pathologists who rely upon a medical renal biopsy as their diagnostic modality. They extrapolate findings from a tiny tissue sample to the entirety of both kidneys although the possibility of unilateral or segmental disease must be entertained. Conversely, surgical and urologic pathologists largely rely upon a copious tissue sample, a partial or complete nephrectomy, to characterize a disease that is often unilateral in nature.
Renal pathologists and surgical pathologists have different requisite gross and histologic understanding of the kidney because of the divergent specimen types and disease spectrum they encounter. Several recent publications have highlighted important medical renal diseases present in a tumor nephrectomy that may convey greater prognostic importance than the indication for nephrectomy.4,5 Conversely, a medical renal biopsy may reveal a urologic disease normally diagnosed on a nephrectomy specimen or at autopsy.
This review initially focuses upon architectural features of the kidney and its environs whose understanding may explain the occasional occurrence of nonrenal organs in a renal biopsy and may enhance insight into renal anatomy-related nonrepresentative biopsy findings. The frequency of inadvertent biopsy of nonrenal organs was assessed by searching the Arkana Laboratories data base to identify biopsies that included liver, spleen, adrenal, pancreas, small bowel, and colon. This section is followed by a discussion of 2 urologic diseases, herein defined as a disease in which a nephrectomy is required to fully understand, that may appear in a medical renal biopsy. This includes (1) cysts and cystic kidney diseases and (2) renal neoplasms. The frequency of encountering a renal cyst or an incidental neoplasm was assessed by searching the Arkana Laboratories data base for key terms cysts, multicystic and polycystic, and carcinoma, adenoma, papillary, metastatic, lymphoma and leukemia, respectively. The reports were reviewed for pertinent demographic and clinical information. It is hoped this large biopsy experience will broaden understanding of the full spectrum of kidney diseases encountered in a medical renal biopsy.
RETROPERITONEUM AND PERIRENAL ENVIRONMENT
The kidneys reside in the retroperitoneum in close proximity to multiple organs (Fig. 1). The retroperitoneum is divided into 3 fascia-invested compartments: anterior pararenal, perirenal, and posterior pararenal spaces.6,7 The posterior pararenal space contains fat but no organs. In the obese patient the quantity of fat can be formidable complicating performance of a renal biopsy.
The perirenal space is enveloped by the Gerota fascia. It contains the kidneys, ureter and renal pelvis, adrenal glands, aorta, vena cava, and lymph nodes cushioned by perinephric fat. The perirenal space is bounded medially by dense adventitial connective tissues of the aorta and vena cava that impede contralateral spread of perinephric urine leaks, hemorrhage, infection, and neoplastic infiltration.7
The anterior pararenal space contains the pancreas and duodenal loop medially and ascending and descending colon laterally (Fig. 1). It thins over the kidneys so that only a thin layer of fat may separate the kidneys from the peritoneum. The kidneys are in proximity to 4 intraperitoneal organs, duodenal loop, pancreas, spleen on the left, and liver on the right (Fig. 1). Knowledge of the perinephric neighborhood is important when performing a renal biopsy as these organs are occasionally sampled. Fortunately, the vena cava and aorta located anterior to the vertebral bodies are usually secure from inadvertent biopsy. In a review of 44,000 Arkana Laboratories medical renal biopsy reports 75 cases (0.17%) contained one or more nonrenal organs (Table 1). Although, complications developing when a wayward needle encounters a perinephric organ appear negligible, the clinician should always be notified of the finding.8,9
The kidney has a 1 to 2 mm dense fibrous capsule investing its peripheral aspects and 2 perinephric fat compartments.1,3 The peripheral perinephric fat is located between the Gerota fascia and the renal capsule. Its quantity varies substantially between individuals. It can be involved in a variety of inflammatory and neoplastic processes. The perinephric tissue as well as any associated blood in a biopsy merit examination as they may rarely contain important diagnostic findings such as a soft tissue tumor (angiomyolipoma, liposarcoma, etc.), amyloid deposits, or a hematopoietic neoplasm that may not be present in the renal tissue (Figs. 2A, B).
The second perinephric fat compartment is the renal sinus defined as the space between the pelvicalyceal system and the renal parenchyma. The sinus has a complex 3-dimentional structure due to forniceal extensions containing fat and interlobar vessels that invest the pyramids and minor calyces.10 As the pyramids and minor calyces angle toward the collecting system from the anterior and posterior plane, in a bivalved kidney or in a renal biopsy sinus tissue may appear completely surrounded by renal parenchyma (Figs. 3A, B). Evaluation of the renal sinus is critical in tumor staging as it represents the primary site of extrarenal extension for pediatric and adult renal cancers.11–13
Sinus tissue can be distinguished from capsule and perinephric tissue in a renal biopsy. The renal capsule consists of dense fibrous tissue with a laminar organization (Fig. 4A). The peripheral perinephric fat contains small arteries and veins and no nerves. Conversely, sinus tissue contacts directly the parenchyma of the inner medulla or cortical column of Bertin without a fibrous capsule. The sinus contains loose unorganized connective tissue and fat. In contrast to the peripheral perinephric fat, nerves and large arteries, and veins may be present (Fig. 4B).
RENAL LOBAR ARCHITECTURE
The kidney has a lobar architecture with an average of 14 lobes per kidney. Each lobe consists of a tapering cone of renal medulla surrounded by a cap of renal cortex.1,3 The lateral cortical interfaces of a lobe form the columns of Bertin whose glomeruli drain in opposite directions. Renal lobes may be single (simple) or fused (compound). Compound pyramids drain more than one lobe. They are concentrated at the poles and have a concave pelvic surface. This architecture results in susceptibility to intrarenal reflux with infection and/or obstruction because their ducts of Bellini open under pressure in contrast to simple pyramids whose ducts close. As the lower pole is usually the target of a medical renal biopsy, in reflux-related disease biopsy findings may not be representative of the kidney elsewhere or the contralateral kidney. Furthermore, 2 separate cores of cortex can look radically different if they sample adjacent simple and compound pyramids in a reflux-related disease (Figs. 5A, B).
RENAL LYMPHOVASCULAR CONNECTIONS
Vascular disease is the most common cause of acute and chronic kidney injury. Vascular-related lesions may be focal in a biopsy or affect the entire specimen. The vascular supply to kidney provides an anatomic basis for these possibilities. There are many variations in renal artery and vein organization but a few generalizations apply.14,15 The main renal artery divides into 5 segmental arteries. An upper pole and lower pole segmental (polar) artery supplies the anterior and posterior of each pole. A polar artery may also arise also directly from the aorta to supply a polar region. This occurs in 20% to 30% of patients.
All renal arteries are end arteries lacking collateral connections. Therefore, the size of a vascular lesion is a guide to the caliber of artery affected. This can be estimated when the entire kidney is available.3 In a renal biopsy the extent of renal involvement cannot be precisely determined but inferences can be made about the artery involved. Focal or multifocal cortical infarction with portions of uninvolved cortex indicates peripheral interlobular artery disease because an interlobular artery branches one or more times in the cortex (Fig. 6). Conversely, transcortical infarction, especially if associated with medullary infarction, implicates involvement of an arcuate artery or larger artery. An isolated inner medullary infarct without cortical involvement results from spiral artery occlusion. Spiral arteries arise from interlobar arteries and supply the papillary tips.
A vascular lesion in a renal biopsy, even if diffuse, may result from isolated polar artery lesion and may not be representative of the kidney(s) elsewhere even when multiple cores are affected. An example is a transplant biopsy with total infarction in a patient with only mild renal impairment suggesting that a polar segmental artery was missed during harvesting or transplantation. Conversely, multiple cores sampling adjacent arterial beds may show different findings, normal and infarcted or ischemic, if an occlusive lesion involves one artery bed but not an adjacent one.
Renal veins, unlike veins in other organs, lack a smooth muscle media, in effect, resembling dilated capillaries (Fig. 7). This may facilitate accommodation of their massive flow demands. The kidneys comprise <1% of the body weight yet receive 20% of the cardiac output. The renal venous return is voluminous as 99% of the glomerular filtrate is reabsorbed.
Venous-related disease is unusual in a renal biopsy as renal veins, unlike renal arteries, have extensive collateral connections. However, with main renal vein thrombosis bland fibrin thrombi and/or neutrophils may occasionally be seen in glomerular capillaries.
Knowledge of venous anatomy is important for surgical pathologists when evaluating a renal neoplasm for staging purposes.13 The interlobar veins enter the renal sinus between renal pyramids. The posterior sinus veins cross over the minor calyces anterior to the renal pelvis and converge with the anterior veins to form a venous plane (Fig. 8). The largest sinus veins are usually 1 to 2 cm in diameter but can become much larger when involved by tumor. As most renal cell carcinomas (RCCs) metastasize by extension into these large veins, examination of the anterior venous plane is required for tumor staging.13
Tumor dissections along the anterior venous plane led to the recognition of retrograde venous invasion.16 Retrograde venous invasion occurs when the main renal vein is occluded by tumor leading to retrograde growth within venous tributaries draining the non-neoplastic cortex (Fig. 9). Tumor can sequentially involve interlobar, arcuate, and interlobular veins. In a bivalved specimen this process is easily mistaken for multiple primary tumors because continuity with the main tumor may not visible due to the circuitous route the veins travel.
The main renal vein is formed by confluence of the segmental veins near the renal hilum.17,18 It has multiple systemic connections relevant to metastases of renal cancers (Fig. 10). The main renal vein connects to lumbar veins posteriorly, the hemiazygous veins on the left, azygous veins on the right, gonadal, and common iliac veins inferiorly.19 The lumbar veins at each intervertebral disk connect to the vertebral venous system, a venous labyrinth with longitudinal sinuses that extends along the entire spinal column. Inferiorly, the vertebral venous system communicates with sacral, pelvic, and prostatic veins. Superiorly, it communicates with the intracranial venous system consisting of the cortical veins, dural sinuses, cavernous sinuses, and ophthalmic veins. The subsequent venous drainage of the intracranial system ultimately flows into the jugular veins and then the superior vena cava.
Batson20 in 1940 employed intravenous injection with x-rays and demonstrated that the vertebral venous system is a low pressure, large capacitance valve less system that permits bidirectional blood flow. Changes in intracranial pressure due to straining, coughing or sneezing, result in blood flow from intrathoracic, abdominal, and retroperitoneal veins into the vertebral vein and the intracranial venous system. Blood flow reverses repeatedly during the day. Thus, renal cancers can spread to the pelvic bones and organs, the vertebral skeleton, and demonstrate the seemingly paradoxical behavior of bypassing the heart and lungs to metastasize to the skull, brain, and head and neck sites.20 Batson commented about the vertebral venous system “we have a vast intercommunicating system of veins … constantly and physiologically the site of frequent reversals of flow. During these reversals a pathway up and down the spine exists which does not involve the heart or lungs. It provides a ready vehicle for the explanation of ‘aberrant’ metastatic patterns.”21
The kidney has a rich lymphatic drainage that begins in the connective tissue investment of peripheral interlobular arteries and veins.22 Although cortical lymphatics are usually smaller than the adjacent veins, they resemble cortical veins and capillaries as they also lack smooth muscle (Fig. 11). Cortical lymphatics drain toward the medulla and enter the sinus. In the normal kidney no, or only rare lymphatics exist among glomeruli, cortical tubules or in the medulla. However, neolymphangiogenesis occurs in these sites with diverse inflammatory processes.22
Most lymph exits the renal sinus through the hilum. There are also lymphatics in the pelvic muscularis allowing an alternate pelviureteral flow. The primary locoregional drainage is to the hilar lymph nodes although only 15% to 24% of radical nephrectomies have lymph node tissue identified even when all of the hilar fat is examined histologically.23–26 Hilar lymph most often goes to one or more nodal stations that surround the aorta and vena cava. From there lymph can follow 3 parallel tracks up or down the aorta and the vena cava as illustrated in the drawing from lymphatic injection studies of Parker in 193524 (Fig. 12).
Lymphatic metastases are capricious because lymph flow is as well. Lymph may flow to the hilar lymph nodes, bypass the hilar nodes and travel directly to the aorto-caval nodes, or bypass both nodal stations and involve thoracic lymph nodes or pelvic nodes. This explains why only one third of RCC patients with positive locoregional nodes will have positive hilar lymph nodes.25,26 Lymph node metastases may even proceed directly to the thoracic duct and into the left brachiocephalic vein to become hematogenous. The unpredictability of lymphatic spread may explain the infrequent use of regional lymph node dissection in RCC treatment and sentinel lymph node biopsy in operative staging of RCC which is technically feasible.27–29
RENAL CYSTS AND CYSTIC KIDNEY DISEASES
Cysts are the most common cause of a renal mass noted on abdominal imaging.30–34 Most are benign cysts, but complex cysts and cystic kidney diseases also occur. Cysts may also be encountered as a microscopic finding in a medical renal biopsy. In a search of 44,000 consecutive renal biopsy reports at Arkana Laboratories renal cysts were sufficiently prominent to merit mention in 147 cases (0.3%).
Cysts in a renal biopsy pose a diagnostic challenge as there are so many types of cysts and cystic kidney diseases.35,36 They include nongenetic and genetic causes. The nongenetic causes include a miscellaneous collection of entities such as simple cortical cysts, acquired cystic kidney disease, isolated polycystic kidney disease and lithium-associated cysts.
Genetic causes fall into 2 broad categories. The first is mutation of one or more “Master” developmental genes that give rise to congenital anomalies of the kidney and urinary tract (CAKUT) of which a cystic kidney is but one type of anomaly.37–39 These are common occurring in ∼10% of the population and accounting for up to 50% of renal failure in children. They present in syndromic and sporadic contexts, the latter being most common. CAKUT may affect a single kidney-lower urinary tract unit with a completely normal contralateral kidney, or may show bilateral anomalies that differ in type, even with a germline mutation that might be expected to act similarly on both kidney-lower urinary tract moieties (Table 2).
The second genetic cause is mutation of a ciliary gene (>60 genes identified) giving rise to a ciliopathy (Table 3). Ciliopathy genes encode for proteins crucial to the formation and function of the primary cilium of renal tubular cells and extrarenal epithelium.40–42 The primary cilium is a slender organelle that originates from the basal body and extends from the apical surface of most renal epithelial cells including parietal epithelium. It was long regarded as a vestigial structure but is now known to have critical sensory and cell signaling functions that affect cell differentiation, proliferation, and polarity.
The ciliopathies are clinically and pathologically diverse. Inheritance patterns include autosomal dominant, autosomal recessive, and X-linked. The kidneys may be developmentally normal at birth and later develop cysts, or may be are abnormal at birth with cysts and metanephric dysgenesis (renal dysplasia) indistinguishable for some CAKUT abnormalities. Some result in a tubulointerstitial nephritis with occasional cysts while others result in cystic kidney disease with a neoplastic diathesis. All have extrarenal components.
The American Academy of Pediatrics, Section of Urology, established terminology for cystic kidneys as shown in Table 4.43 Notice that a cyst does not need to be spherical or completely enclosed. Nor does it have to be large, only 200 µm or more, the size of an adult glomerulus and Bowman’s capsule. This is well below the 1 to 2 mm threshold of for radiographic imaging of a cyst. A cystic kidney does not necessarily connote a cystic kidney disease, that is, a disease related to cysts. Also note that a polycystic kidney is not just a kidney with multiple cysts, rather, it indicates a genetic cystic kidney disease.
Cyst evaluation is most straightforward in a nephrectomy specimen or at autopsy compared with a renal biopsy because the number, location and laterality of cysts, the histology of the cyst lining and the noncystic parenchyma are easily assessed, and the family history is often known. Cysts on a biopsy often elicit more questions than answers because of limited morphologic and clinical data. In general, cysts detected in a pediatric biopsy are more ominous than in an adult because a genetic disease is likely. My approach to the classification of cystic kidneys begins with a topographical approach supplemented by anatomic and clinical information as listed in Table 5. An algorithm for this approach is provided (Table 6).
The cyst topography algorithm was designed for a nephrectomy or autopsy kidney but may also be helpful with a renal biopsy. It does not capture all the nuances and possibilities but provides a starting point. Notice that multiple entities are repeated in first 3 categories, infrequent cysts, unilateral numerous cysts, and bilateral numerous cysts. This was done for 2 reasons. First, there is a spectrum of disease severity for many entities. For instance, renal dysplasia varies from clinically insignificant occasional cysts, to unilateral cysts, to severe lethal bilateral multicystic dysplasia. Second, cyst progression is inherent in several cystic diseases such as acquired cystic kidney disease, autosomal dominant polycystic kidney disease, von Hippel-Lindau disease, tuberous sclerosis complex and in patients on lithium therapy. Initially mild and clinically insignificant cysts may progress over years or decades to cystic kidney disease.
Only a few cystic diseases have both cortical and medullary cysts. This includes acquired cystic kidney disease, autosomal dominant polycystic kidney disease, autosomal recessive polycystic kidney disease and lithium-associated cystic disease.44–59 Cysts limited to the medulla are uncommon but occur in only a few situations, childhood/young adult presentations of autosomal recessive polycystic kidney disease, medullary sponge kidney (history of nephrolithiasis), nephronophthisis, and autosomal dominant tubulointerstitial diseases (formerly known as medullary cystic kidney disease) due to UROM, MUC1, REN, and HNF1β mutations.56–63 Cysts in the latter 2 diseases do not affect all patients. If cysts develop they are usually seen in the advanced stages of disease and rarely present at the time of renal biopsy.
The combination of cysts and solid tumors also has a limited differential although simple cysts and a renal tumor may coincidentally be present.64–75 There are 3 cystic kidney diseases with a significant neoplastic diathesis acquired cystic kidney disease, von Hippel-Lindau disease, and tuberous sclerosis complex (Table 7). Recently chronic lithium therapy also has been associated with an increased risk of renal neoplasms, both benign and malignant.74,75 Some would also include autosomal dominant polycystic kidney disease to this list, but evidence is limited and no large population-based studies have been reported to indicate an increased risk of RCC.
BOSNIAK CLASSIFICATION OF RENAL CYSTS
A simple cortical cyst is the most common type of renal cyst.76–78 A simple cyst must be radiologically distinguished from a complex cyst that has septations, calcifications, solid areas, or shows enhancement, findings that may indicate malignancy. This issue is addressed with the Bosniak Renal Cyst Classification.79–81 In 1986 Bosniak proposed a classification of renal cysts based upon x-ray computed tomography findings into 4 types, types I to IV, intended to distinguish benign and likely benign cysts (type I and II) from cysts suspicious for malignancy (type III) or clearly malignant cysts (type IV). The classification was modified in 1997 with the addition of type IIF (F for follow-up) to reduce the number of benign lesions in the type III category. This classification is widely used by radiologists and urologists to stratify patients into a surgical group (types III and IV) and a nonsurgical group (types I and II), with a third group (type IIF) requiring follow up at 3 to 6 months intervals. Major entities that present as a Bosniak type IIF, III, and IV complex cyst are listed in Table 8.
MOST COMMON RENAL CYSTS
The 4 most common types of cysts encountered in a renal biopsy are simple cysts and cysts developing in acquired cystic kidney disease, autosomal dominant polycystic kidney disease, and chronic lithium therapy (Table 10). There is only one medical renal biopsy study of renal cysts.48 Liu and colleagues in a review of 720 biopsies found “microcysts” in 21 cases (2.9%). The cysts were regarded as acquired because all patients had chronic kidney disease and autosomal dominant polycystic kidney disease was excluded clinically. The cell lining ranged from flattened to low cuboidal based upon images provided. As no cysts were noted on x-ray computer tomography examination of 20 patients they would not carry a clinical diagnosis of acquired cystic kidney disease. Thus, the presence of cysts on a renal biopsy may indicate a cystic kidney but not necessarily a cystic kidney disease.
A simple cyst (type 1 Bosniak cyst) is usually asymptomatic, unilocular and exophytic.76–78 Occasionally it may have thin septa (type 2 Bosniak cyst). They are uncommon before the age of 40 but increase in prevalence, number and size with advancing age. Half of individuals over the age of 50 have a simple cyst and one third will have multiple simple cysts. Historically simple cysts have been regarded as incidental. Recent evidence, however, indicates a frequent association with hypertension, small kidneys and chronic kidney disease especially when large and multiple.82
A simple cyst is lined by a uniform flattened to low cuboidal epithelium, or if large, may have no cell lining (Fig. 13). A small simple must be distinguished from an empty Bowman’s capsule or a cortical vein which may appear similar because of their flattened cell lining. Cysts identical to simple cysts are seen in autosomal dominant polycystic kidney disease and acquired cystic kidney disease but cysts with other types of cell lining are also present. In general, in an adult over the age of 40 autosomal dominant polycystic kidney disease is unlikely if only 1 to 2 radiologically identified cysts are present. Acquired cystic kidney disease can be excluded if advanced chronic kidney disease is absent.
Acquired cystic kidney disease is defined as the presence of 3 or more renal cysts in a patient with advanced chronic kidney disease not due to a cystic kidney disease.44–49 In end stage kidneys the incidence of acquired cystic kidney disease, and the number and size of cysts increase with duration of dialysis. By 10 years 90% of patients will have acquired cystic kidney disease. However, up to 8% of patients may develop acquired cystic kidney disease before initiation of dialysis. Thus, acquired cysts are not uncommon in a medical renal biopsy in a patient with chronic kidney disease.
Cysts in acquired cystic kidney disease develop in both cortex and medulla, and involve proximal and distal tubules, and collecting ducts. By definition, they are associated with significance tubulointerstitial scarring (Figs. 14A–C). The cyst lining is morphologically diverse ranging from a flattened or cuboidal simple cyst-like lining to a columnar cell lining resembling normal proximal tubule, distal tubule or collecting duct. Some cysts may have an exuberant lining with enlarged clear cells, eosinophilic cells, vacuolated cells or foamy cells. Tubular ectasia may be seen in nonscarred cortex that may represent cysts in evolution (Figs. 14B, C). Calcium oxalate crystals or calcium phosphate deposits may be encountered in the interstitium or in cyst epithelium (Figs. 13B, C). Renal neoplasms may also be seen as they develop in up to 10% of patients with acquired cystic kidney disease.64–67
The exuberant cyst cell lining in acquired cystic kidney disease may be “atypical” with large nuclei and prominent nucleoli or show cell stratification or papillary formations, cytologic alterations that have been shown to correlate with some of the RCC types encountered in end-stage kidneys (Fig. 14D).46,47 As some end-stage kidney-associated RCCs and some sporadic RCCs are cystic, when a cyst with an exuberant cell lining is encountered on a medical renal biopsy this could represent a benign, although possibly neoplastic cyst, or be part of cystic RCC if solid areas are present elsewhere. Ultimately imaging studies will be the final determinate.
The most common genetic kidney disease is autosomal dominant polycystic kidney disease with an incidence of 1:500 to 1000.83–85 In autosomal dominant polycystic kidney disease, like acquired cystic kidney disease, cysts form in the cortex and medulla. The cysts in autosomal dominant polycystic kidney disease, in contrast to acquired cystic kidney disease, initially form in normal appearing cortex (Fig. 15A). Cysts arise from all segments of the nephron, including Bowman’s capsule, and from collecting ducts. Bowman’s capsule involvement is particularly common in children and enters into the differential of a glomerulocystic kidney.3
The cysts in autosomal dominant polycystic kidney disease may have a flattened to low cuboidal cell lining similar to simple cysts and cysts in acquired cystic kidney disease (Figs. 15A–C). Cysts with exuberant cell proliferation of acquired cystic kidney disease do not occur. However, cysts with focal papillary tufts composed of a uniform low cuboidal epithelium with small uniform nuclei that lack atypia or mitotic activity occur and appear unique to autosomal dominant polycystic kidney disease. They have been reported in up to 25% of nephrectomy specimens (Fig. 15D). These usually involve large cysts and are rarely encountered in a renal biopsy. Oxalate crystals are usually not present in autosomal dominant polycystic kidney disease, but focal calcification may be seen. The clinical features of a positive family history for autosomal dominant polycystic kidney disease or markedly enlarged cystic kidneys support the diagnosis of autosomal dominant polycystic kidney disease. However, 15% to 25% of cases represent new mutations so a family history may be lacking. Infrequent small cysts, often clustered because they affect a single nephron, are present in early stages of the disease so renal enlargement may not be present. Although, the presence of multiple bilateral cysts in patient over the age of 40 may indicate autosomal dominant polycystic kidney disease, multiple simple cysts, and acquired cystic kidney disease must also be considered. The location of the cysts can help as simple cysts do not form in the medulla. The absence of chronic kidney disease argues against acquired cystic kidney disease.
Lithium-associated cysts have been reported in 63% of medical renal biopsies in patients on long-term lithium therapy (average13.6 y).54,55 They form due to an antiapoptotic effect of lithium. The cysts appear before onset of lithium-associated chronic kidney disease which may develop in up to 15% of patients. The cysts involve cortex and medulla and are usually small, 1 to 3 mm on imaging studies. The cyst cell lining consists of a uniform appearing low cuboidal epithelium with cytoplasmic clearing resembling collecting ducts (Figs. 16A, B). The cysts have a distal tubule/collecting duct immunophenotype based upon epithelial membrane antigen and lectin staining. The cysts may show pericystic fibrosis and most frequently occur in zones of tubulointerstitial scarring. The key microscopic findings of the four most common renal cysts are compared in Table 9.
Many other types of cysts may rarely be encountered in a medical renal biopsy. For instance, occasionally a patient with a history of autosomal recessive polycystic kidney disease, renal dysplasia, von Hippel-Lindau disease or tuberous sclerosis complex may be biopsied. The cysts in children with mild forms of autosomal recessive polycystic kidney disease will typically have primarily medullary cysts with few or no cortical cysts.3 The cysts may be rounded in contour and may be associated with interstitial fibrosis resembling autosomal dominant polycystic kidney disease. The cysts in metanephric dysgenesis of a dysplastic kidney may have a diverse appearance including glomerular cysts, cystic immature ducts, and large cysts with pericystic fibrosis.3 Lower urinary tract abnormalities will usually be present and extraurinary tract malformations may also be present. The cysts in von Hippel-Lindau disease are invariably lined by clear cells while the cysts of tuberous sclerosis complex typically are lined by large densely eosinophilic cells.68–73 Unfortunately, many renal cysts will remain unclassified because of overlapping histology between different diseases and incomplete clinical information as previously noted.
INCIDENTAL DETECTION OF A NEOPLASM ON A MEDICAL RENAL BIOPSY
The incidental detection of a renal mass in patients with abdominal imaging for a nonrenal indication is common, occurring in 14% to 40% of patients having x-ray computer tomography.30–34 The most common mass is a benign cyst classified according to cyst complexity using the Bosniak Renal Cyst Classification as previously discussed. Solid lesions are usually neoplasms, most commonly a RCC, but are difficult to definitively classify by imaging study alone. For instance, RCCs of the various types cannot be distinguished from one another, nor distinguished from a benign oncocytoma or a myoid predominant (fat poor) angiomyolipoma. The incidental detection of a small RCC on abdominal imaging accounts for the increased incidence of RCCs observed over the past decade. This is important because an incidentally detected RCC has a much better prognosis than a symptomatic RCC.30
The incidental detection of a neoplasm in a medical renal biopsy also occurs, albeit infrequently, in 0.2% to 0.5% of biopsies (Table 10). The only report of incidental neoplasms on a medical renal biopsy identified 25 RCCs in a review of 11,880 cases (0.2%)86; 22 were classified as papillary RCC. However, since that publication many other types of RCCs have been defined, therefore, some might be classified differently today. Most RCCs encountered in biopsies are from adults over the age of 50 with chronic kidney disease possibly because chronic kidney disease and renal neoplasms have risk factors in common such as smoking, hypertension, obesity, and diabetes mellitus.87
A needle biopsy of a clinically detected renal mass has excellent diagnostic accuracy in distinguishing a benign from a malignant tumor (>90%), not surprising as RCCs account for ∼80% of solid lesions.31,88,89 This accuracy, however, does not necessarily translate to the incidental detection of a renal tumor in a medical renal biopsy. As a mass was not targeted by a medical renal biopsy only a small fragment of tumor may be present with most of the specimen represented by non-neoplastic kidney. In addition, the tumor may be limited to the tissue for immunofluorescence or electron microscopy comprising morphologic detail.
A small tumor fragment in a medical renal biopsy may represent a clinically insignificant tumor or represent the edge of a large clinically significant tumor with tumor size is the most important determinate. Unfortunately, tumor size cannot be established by biopsy and size information is rarely available as ultrasound used for medical renal biopsy is insensitive in mass detection. Furthermore, if a nephrologist performed the biopsy they are inexperienced in tumor recognition. Tumor size is important for several reasons. It is a major defining criteria to distinguish a papillary adenoma (<1.5 cm) from a papillary carcinoma, the most common type of tumor identified in a medical renal biopsy (Table 10).90 Size also has prognostic importance, the smaller the mass, the greater the likelihood it is a benign tumor. Forty percent of solid masses <1 cm are benign, while tumors 4 cm or larger the percentage drops to 10%.30,31 Finally, size correlates with likelihood of extrarenal extension and metastatic disease, and influences clinical management decisions such as active surveillance versus surgical intervention. Active surveillance is often recommended for masses 1 cm or less.30–32
The American College of Radiology Incidental Findings Project published management recommendations for an incidental renal mass detected on x-ray computer tomography.30 However, there are no published guidelines for renal pathologists on the approach to an incidental neoplasm detected in a medical renal biopsy. This situation is more problematic as many renal pathologists do not sign out surgical specimens, thus, their experience in tumor diagnosis may be limited. Although a detailed discussion of the diagnostic nuances of renal tumor diagnosis is beyond the scope of this review, a broad overview with a few recommendations will be offered.
Primary renal epithelial neoplasms are the most common incidental tumor encountered in a medical renal biopsy (Table 10). However, hematopoietic neoplasms, mesenchymal tumors, and metastatic cancers also occur, and a contaminate (“floater”) from another case must also be considered (Table 11). A contaminate should be considered if the tumor is not directly attached to kidney tissue. This is particularly of concern if the pathology laboratory does not have a grossing station dedicated for renal biopsies. If the tumor is attached to kidney tissue or a mass was noted on imaging, a floater can be excluded. If not, further investigation may be required.
A metastasis is the least common category of tumor in a medical renal biopsy. In a review of 20,000 consecutive cases at Arkana Laboratories 7 nonhematopoietic metastases were identified including urothelial carcinoma (0.035%). With a metastasis a history of a nonrenal primary will usually be present as a renal presentation for a carcinoma primary elsewhere is very uncommon.91–93 Most clinically detected renal metastases are solitary and unilateral, mimicking a renal primary. The time between diagnosis of the primary and detection of a renal metastasis may be as long as 5 to 10 years. Lung, ear, nose and throat, and gastrointestinal tumors are the most common solid malignancies reported but many other primary sites may be seen.91–93 The most common RCCs and many metastatic tumors may have a distinctive histology allowing definitive diagnosis. Desmoplasia is a common finding with a metastasis but also occurs with collecting duct carcinoma and when urothelial carcinoma extends into the kidney (Fig. 17). PAX8 can be employed to implicate a renal primary as it is expressed in all RCC subtypes with a sensitivity of 95%.94 However, other carcinomas, especially urothelial carcinoma and B-cell lymphomas may also be PAX8 positive so cautious interpretation is required.
Although most primary renal epithelial neoplasms are carcinomas, a benign epithelial neoplasm should also be considered. There are only 4 benign primary renal epithelial or mixed epithelial and stromal tumors, papillary adenoma, oncocytoma, metanephric adenoma and the mixed epithelial and stromal family of tumors.95 In principal, excluding these 4 entities means an epithelial neoplasm is malignant by default, either primary or metastatic.
Papillary adenoma is most common of the 4 benign neoplasms and is particularly common in patients with advanced chronic kidney disease. It is defined as an unencapsulated tumor with a papillary or tubulopapillary architecture, low nuclear grade, and <1.5 cm diameter (Fig. 18A).90 Conversely, high nuclear grade, lack of circumscription and presence of a pseudocapsule can support a malignant possibility on a medical renal biopsy. If the tumor is too small to image by magnetic resonance imaging or x-ray computer tomography scan then it will be below the 1.5 cm papillary RCC threshold. However, it must be noted that papillary architecture occurs in other types of RCC where size is not relevant to a carcinoma designation, such as clear cell papillary RCC, the MiT-TFE translocation carcinomas, oncocytic papillary RCC, and clear cell RCC with pseudopapillary growth pattern.95,96
Oncocytoma is the second most common benign epithelial neoplasm. It has a distinctive histology with densely eosinophilic granular cytoplasm, low nuclear grade, absent mitoses, and a distinctive CK7 staining pattern with scattered intensely positive cells (Fig. 18B). However, focal nuclear pleomorphism may be present and similar oncocytic appearing cells occur in the eosinophilic variant of chromophobe RCC, oncocytic papillary RCC and oncocytic angiomyolipoma.
Metanephric adenoma is a rare neoplasm with an embryonal tubulopapillary appearance that must be distinguished from a solid papillary adenoma/solid low grade papillary RCC and Wilms tumor. Immunohistochemistry is very helpful. Papillary adenoma is CK7 and AMACR positive and WT-1 and CD57 negative while metanephric adenoma stains the converse. Wilms tumor is WT-1 positive but negative for the other 3 stains.
The mixed epithelial and stromal family of tumors family of tumors includes mixed epithelial and stromal tumor and cystic nephroma. They arise deep in the kidney, often involving the medulla. Both have stromal cells that stain for estrogen and/or progesterone receptor. Cystic nephroma is diffusely cystic with a flattened to hobnail cell lining while mixed epithelial and stromal tumors has solid areas which may contain fat or smooth muscle and its epithelium can be flattened, hobnail, columnar or stratified.
Once a tumor in a medical renal biopsy is identified as a RCC the diagnosis of the subtype can be challenging. Clear cell RCC, papillary RCC and chromophobe cell RCC comprise over 90% of cases which skews the initial differential. They usually have distinctive histologic features (Figs. 19A, B). However, the World Health Organization currently recognizes 13 distinct RCC subtypes and an unclassified RCC category and there are several additional RCC subtypes widely accepted but not yet fully vetted by the World Health Organization (Table 12).95 Furthermore, the epitheliod angiomyolipoma mimics an epithelial neoplasm. As there is considerable morphologic variation within a given RCC type and overlapping morphologic features between many RCC types, when a tiny fragment of a tumor is sampled a cautious approach to subtyping is recommended.
Immunohistochemical stains can help simplify the differential diagnosis of a RCC subtype but there are few diagnostically unique immunohistochemical profiles.94–98 The use of immunohistochemistry for classification is driven by cell phenotype (clear cells, eosinophilic cells, distal nephron/collecting duct-like carcinoma cells, sarcomatoid cells) or papillary architecture. In principal, molecular testing could also play a role.96–98
Hematopoietic neoplasms, both lymphoproliferative disorders and leukemias, are second to epithelial tumors as an incidental neoplasm (Table 10) (0.012%). They may represent a primary renal lymphoma, or a renal presentation of a lymphoma or leukemia subsequently identified elsewhere or already known.99–102 Of the 24 cases identified in this series 13 were not known to have a hematopoietic neoplasm before medical renal biopsy. A primary renal lymphoma may seem unlikely since the kidney is devoid of native lymphoid tissue. However, many well documented cases have been reported and primary renal lymphoma represents 0.7% of extranodal lymphomas in North America.101,102 Most are large B-cell lymphomas.
There are several patterns of renal involvement by a hematopoietic neoplasm. Rarely, it will present as a mass lesion resembling a RCC on imaging.100 Incidental involvement on a medical renal biopsy may present as diffuse expansile interstitial infiltrates with relative preservation of tubules and glomeruli, intravascular infiltrates involving peritubular and/or glomerular capillaries or focal interstitial, capsular or perirenal fat lymphocytic infiltrates. Renal failure will usually be present in the first 2 presentations.
Diffuse interstitial involvement is usually easily recognized as a hematopoietic neoplasm. The infiltrate is discohesive and lacks architecture. It may be monotonous or markedly pleomorphic. It expands the interstitium surrounding and separating intact glomeruli and tubules (Fig. 20A). The intravascular forms fills and often distends glomerular and peritubular capillaries by large atypical cells (Fig. 20B). However, the differential includes an intravascular presentation of melanoma and high-grade carcinoma which can easily be resolved by immunohistochemistry. Although focal lymphocytic infiltrates are a typical finding in areas of scarring, they are usually ill-defined and have a polymorphous cellular composition. The presence of one or more well defined foci composed of a monotonous population of cells or the presence of capsular and perinephric fat lymphoid infiltrates should prompt consideration of a lymphoproliferative disorder (Figs. 21A–C). A simple screening approach for both obvious and suspicious cases of a lymphoproliferative disorders is to perform a CD3 and CD20 stain with 10 unstained slides cut at the same time. If there is no history of a lymphoproliferative disorders and there is a marked B-cell or T-cell predominance, or if there are obvious cytologic features of malignancy, consultation with a hematopathologist is initiated for final classification. The 10 unstained slides will usually suffice for a preliminary evaluation of the process.
The most common mesenchymal tumor in a medical renal biopsy is an angiomyolipoma (Table 10).103–105 This is not surprising as 8% to 12% of unselected autopsy kidneys thoroughly examined have one or more angiomyolipomas.104 An incidental angiomyolipoma may be lipid cell predominant, myoid cell predominant or triphasic with abnormal arteries (Figs. 22A, B). They are usually easily recognized although the uncommon oncocytic and epithelioid types can be diagnostically challenging. Melanocytic markers may be employed in uncertain cases. Sarcomas of renal or perirenal origin occur but are extremely rare in medical renal biopsy. Liposarcoma is the most common type but any sarcoma may arise in, or secondarily involve the kidney (Fig. 2B).
The kidney is affected by the most diverse collection of diseases of any organ system. This includes developmental abnormalities, neoplastic diseases, injury from the most common systemic diseases, hypertension and diabetes, and injury resulting from its filtration and tubular secretory/absorptive functions and its external environmental connection. It is the only organ in which two pathology subspecialties, renal and urologic pathology, and 2 clinical specialties, nephrology and urology, engage in diagnosis and treatment.
A surgical or urologic pathologist focuses on macroscopic kidney diseases although the recent emphasis on medical renal diseases in the non-neoplastic kidney has expanded their diagnostic responsibilities. Conversely, the renal pathologist has a more microscopic focus but macroscopic renal anatomic issues and urologic diseases such as cysts and cystic kidney diseases and neoplastic diseases, periodically enter their diagnostic domain.
Renal cysts and cystic kidney diseases encompass a large number of entities. Although, their recognition or lack thereof on a medical renal biopsy rarely leads to medical treatment issues, they include genetic diseases of importance whose diagnosis may have family consoling implications. Furthermore, with advances in understanding the molecular basis for some genetic diseases, especially the most common genetic renal disease, autosomal dominant polycystic kidney disease, therapies are emerging that may delay the rate of progression making early diagnosis more important.106
Renal neoplasia is a rapidly expanding field with new entities appearing on a regular basis. This coupled with the often limited quantity of tumor when incidentally detected on a medical renal biopsy create great challenges for a renal pathologist. In the final analysis it is most important to simply recognize a lesion as a neoplasm on a medical renal biopsy. This may be particularly difficult if the only tumor present is in the tissue for immunofluorescence or electron microscopy. The issue of contaminate, metastasis versus renal primary, and benign versus malignant tumor must be considered but in conjunction with consultation with a hematopathologist, surgical pathologist or urologic pathologist. The latter consultation is required for all cases in which a diagnosis of malignancy is entertained since Standard of Care requires a new diagnosis of cancer be reviewed by a second pathologist.
Most renal and urologic pathology fellowships have limited, or entirely lack, exposure to their kindred discipline. A significant segment of renal diseases are not, therefore, a formal part of their training programs. However, all fellows will be confronted with the full spectrum of kidney diseases in their clinical practice. This review attempts to bridge this diagnostic divide by first pointing out important anatomic features of the normal kidney, its local environment and its lymphovascular connections that may influence understanding of the findings in a medical renal biopsy. This was followed by review of some of the more common and important urologic diseases that may surface in a medical renal biopsy with general diagnostic strategies provided. It is hoped this may compliment previous publications of medical renal diseases encountered in a nephrectomy specimen. It is also hoped that this may also encourage integration of, or exposure to, urologic pathology in renal pathology fellowship programs, and vice versa, in order to optimize fellowship training.
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