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Nephroblastomatosis--pathologic and imaging characteristics. SA Merchant, PB BadheDept. of Radiology & Imaging, LTM General Hospital, Sion, Bombay.
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 0010707720 Keywords: Child, Child, Preschool, Diagnostic Imaging, methods,Female, Human, Infant, Kidney Neoplasms, diagnosis,pathology,Magnetic Resonance Imaging, methods,Male, Nephroblastoma, diagnosis,pathology,Sensitivity and Specificity, Tomography, X-Ray Computed, methods,Ultrasonography, methods,
Nephroblastomatosis (NB) is a complex abnormality of nephrogenesis and has been defined as the persistence of metanephricblastema into infancy and childhood. The association of independent foci of persistent blastema with Wilms' tumour has been repeatedly documented. Minor degrees of NB are common with unilateral Wilms' tumour and are almost universal in bilateral Wilms' tumours. For this reason, NB is widely accepted as a premalignant lesion[1]. Several forms of NB exist. The spectrum of their pathologic and radio-logic findings is reviewed herein. This review will consider with varying emphasis, virtually all aspects of NB. In the interest of brevity, some aspects will be briefly discussed and acknowledged with appropriate reference citations.
To understand nephroblastomatosis, it would be helpful to review normal developmental anatomy of the kidney. The ureteric bud contacts aggregates of primitive nephroblasts (metanephric blastema) in the paraspinal region of the developing embryo. Renal development occurs as a result of the interaction of the advancing and bifurcating ureteric bud and the metanephric blastema, which lies peripherally in the subcapsular and interlobular spaces. The blastemal tissue causes the ureteric bud to branch and form the collecting system of the kidney, whereas the ureteric bud induces the metanephric blastema to form epithelial and stromal elements of the kidney. Thus nephrons and associated supporting structures arise from the metanephric blastema. As the ureteric ducts migrate peripherally, they are invested by metanephric blastema. The peripheral portions of the kidney are the most recently formed and the juxtamedullary nephrons are the oldest. In the mature kidney, the cortical portion of the lobe is not confined to the surface of the kidney, because the process of fusion of the 12-14 lobes (each with its distinct medullary pyramid and surrounding cortex) during development, produces columns of cortical tissue that extend from the surface to the pericalyceal soft tissue, deep within the kidney (Septa of Bertin). Nephrogenesis is complete in the normal fetus at 34-36 weeks of gestation. Normally thereafter there is no remaining metanephric blastema[2]. Microscopic blastema remnants may be seen in as many as 1% of infants at autopsy[3]. Beyond infancy, persistence of metanephric blastema is abnormal and is the undying feature of a spectrum of clinically and pathologically related conditions that includes Wilms' tumour.
The term nephroblastomatosis was first coined by Hou and Holman in 1961[4] who believed it to be a rare embryonic renal tumour characterised by bilateral, diffuse, neo-plastic proliferation of undifferentiated cells of the metanephric blastema. In reality, it comprises a peculiar, generally poorly recognised complex of congenital dysontogenetic disorders of the Infantile kidney, rather than a neo-plastic process[5] and is encountered in 1% of infantile autopsies[1],[5],[6],[7],[8],[9]. In a 1976 study of pathological lesions in the grossly involved parenchyma of resected Wilms' tumour specimens and surgical biopsies from the opposite kidney, Bove and Mc. Adams[10] described three potentially neo-plastic lesions namely nodular renal blastema, metanephric hamartoma and Wilms' tumourlet along with two mal-formative lesions in glomerular immaturity (sclerosis) and cortical cysts". Wilms' tumourlets represented blastema-rich lesions of sufficient size with a possibility of evolving into Wilms' tumour[2],[6],[10]. However, criteria to subclassify the blastema, indicating its neo-plastic potential, were not recognised. Though in some instances it seemed malignant, microscopically these could also evolve into nephrogenic adenomas[2] or partially matured metanephric hamartomas[1]. Bove and Mc. Adams[10] also suggested that the distribution of NB could have some clinical relevance, i.e. peripheral or superficial cortical lesions with a multi-focal distribution occurred in older children who had Wilms' tumour (often bilateral), as against diffuse pancortical lesions which occurred in early infancy (infantile type) which is rare and has the least malignant potential, as a large solitary Wilms' tumour is rarely associated[1],[8]. A third form (superficial diffuse) was proposed as intermediate between the superficial multi-focal and pancortical, with respect to the age at diagnosis, incidence and likelihood of association with Wilms' tumours[1]. Thus developmentally NB which is a diffuse bilateral process can be divided into: a) Multi-focal (Juvenile) b) Pancortical (infantile) c) Superficial diffuse (late infantile)[12]. Histo-logically, the nephrogenic rests (NR's) in young infants are usually composed of blastema or poorly differentiated tubules, whereas older children show well differentiated tubules set in a sclerotic stromal background, with little or no blastema; known as "sclerosing metanephric hamartoma" preferably "regressing nephrogenic rests". The term "Nephroblastomatosis complex" had been applied to this entire group of precursor lesions and their hyperplastic or neoplastic derivations". Later, in 1988, Beck with suggested a modification in the classification of lesions with respect to their distribution within the renal lobe and classified NB as perilobar, intralobar, panlobar and diffuse Panlobar was synonymous with pancortical, intralobar was within the parenchyma of the kidney while perilobar are lesions on the surface of the kidney and those that lie in the parenchyma corresponding to the septae of Bertin[1],[13]. The NWTS (National Wilms' tumour study) pathological centre has classified NB, in general into 4 groups: 1) Perilobar (cortex) 2) Intralobar (Medullary) 3) Combined (both 1 and 2) 4) Panlobar (rare diffuse type) [Table - 1] tabulates their proposed sub-classification of group 1 - (perilobar). In an attempt to divide lesions into clinically relevant groups, the individual lesions are further sub-classified as dormant, maturing/sclerosing, hyper-plastic and neo-plastic. This requires both gross and microscopic examination. Dormant and sclerosing/ maturing NR's are microscopic, whereas hyper-plastic and adenomatous lesions are macroscopic, plaque like. Any Macroscopic NR that is nodular and enlarges over time is considered neo-plastic[1]. The perilobar type (PLN) can be differentiated from the intralobar type (ILN) as shown in [Table - 2] The perilobar type is commoner[15] (75-80%) 14 than the intra-lobar type (20-25%)[14]. This may be explained on a developmental basis; due to the peripheral portions of the kidney being most recently formed (and therefore more likely to have persistent metanephric blastema) and the juxtamedullary nephrons being the oldest (and therefore less likely to have persistent metanephric blastema). However, ILN represents an earlier defect in nephrogenesis at a time when blastemal potentialities are much more diverse. Thus, Wilms' tumours associated with ILN have a much more diverse morphologic spectrum, with frequent recurrence. Stromal predominance is observed and heterotopic cell types such as skeletal muscle, squamous epithelium are common. Thus one could speak of PLN associated or peri-lobar Wilms' tumour, and ILN associated or centrilobar Wilms' tumour. The two terms representing extreme ends of a developmental spectrum with more than half of all Wilms' tumours failing into an intermediate range 8 of patients with ILN in association with unilateral Wilms' tumour, 16% will develop a metachronous Wilms' tumour in the contralateral kidney[1],[8],[14]. In 1990 Beckwith et al further suggested that all foci of persistent metanephric tissue be referred to as nephrogenic rests (NR's) and that the presence of multiple NR's be termed as Nephroblastomatosis[14]. Grossly NB can be distinguished from a classical Wilms' tumours, which is usually a bulky, spherical mass. occupying one portion of the kidney, whereas NB is usually diffuse and involves the entire subcapsular portion. It has no renal capsule, but its lobulated margin separates it from the underlying uninvolved kidney. It has a uniform, pink, fish-flesh appearance and firm consistency. Areas of necrosis, haemorrhage and macroscopic cysts seen in Wilms' tumours are absent in NB[16]. Before recognition of NB as an entity, similar cases may have been reported as bilateral congenital Wilms tumours, which account for the excellent survival rates in such cases[17]. Microscopically NB comprises of tightly packed monomorphic appearing, nephrogenic epithelial cells, which resemble, to a large extent, the fetal kidney and the nephrogenic zone of the premature kidney. They may differentiate into well differentiated to immature tubules and glomeruli, showing no atypicality and only very rare mitosis. Primitive mesenchyme, cartilage or myogenic cells are absent. Connective tissue element, when present is composed only of interstitial strands and septae of collagen, especially at the periphery of the lesions[16]. Electron microscopy and immunohistochemistry does not help to differentiate NB from Wilms' tumour[16]. Since original observations were made substantial evidence has accumulated to support the concept of NB being a precursor of Wilms' tumour[1],[2],[6],[11],[14]. Following the observation in the third NWTS, NR's were seen in at least 90% of cases of synchronous bilateral Wilms’, tumours[1],[14] with 94% in metachronous bilateral Wilms' tumours. NB has been found in 5 to 7% of cases of multicystic dysplastic kidney, when specifically sought[18],[19] and also in 40-50% of trisomies 13 and 18, and 8% of obstructive uropathies[19],[20].
While blastemal residues or rests have variable histologic findings and neo-plastic potential, there seems to be agreement that macroscopic features of the lesions are useful as predictors of malignancy. Consequently, the role of imaging for initial diagnosis and follow-up of patients with NB needs to be emphasised[1]. Microscopic foci of NB are not identifiable with any imaging modality. In case of macroscopic NB the imaging finding would vary on the type of NB and the imaging modality utilised. Kidneys with NB often have concomitant cystic and dys-plastic malformations of the renal cortex, adding to the difficulty of diagnosis by IVU or US[17],[21]. [Table - 3] attempts to display the possible appearances of the different types of NB on various imaging modalities. Any dominant mass in this setting is a Wilms' tumour and the imaging findings of Wilms' tumours would have to be added over and above those mentioned for NB. The superficial multifocal type usually has a normal sized kidney The WU findings may reveal a lobulated appearance, especially in the nephrographic phase. The appearance on US would be that of multiple small peripheral masses, usually hypoechoic, occasionally hyperechoic. On contrast enhanced CT (CE-CT) these appear as peripheral non-enhancing areas. The surface may reveal lobations. MR would reveal a multiplanar view of the sarrie. It has been reported that post contrast (Gadolinium -DTPA) MR images on T1 weighted spinecho sequences, reveal these masses even more obviously than C E-CT[22]. [Figure - 1], [Figure - 2] & [Figure - 3] The superficial diffuse type would have a mild to moderately enlarged kidney. IVU may reveal an increase in the parenchymal thickness, with the periphery appearing relatively lucent. The surface of the kidney may reveal lobations. The collecting system would be grossly normal. US would reveal a peripheral hypoechoic rim, with the central sinus echo compled being undisturbed. Angiography shows reasonably specific changes[23]. The main renal arteries are normal. The intrarenal vessels are narrowed and stretched at the periphery of the kidneys. The masses are avascular and predominantly in the cortical areas. There may be unusual puddles of contrast material in the renal parenchyma between the nodules. The rind of sub-capsular tissue does not opacify with the nephrogram, and thus there is a scalloped outer margin to the opacified kidney. On CE-CT, confluent. peripheral, non-enhancing areas would be noted. MR with contrast would be expected to reveal these lesions more clearly. The intralobar type would reveal a normal sized kidney. The IVU findings would be normal excepting for a small mass effect that may be caused on the calyx/calyces underlying the usually solitary intralobar mass. USG would reveal a mass, usually hypoechoic., with irregular margins, lying deep within the parenchyma. CE-CT would reveal greater details about this mass, especially its irregular margins. Contrast enhanced MR would be expected to reveal this mass more obviously. The generalised type (pan lobar) would reveal moderate to grossly enlarged kidneys with marked surface lobations. The WU would reveal grossly enlarged kidney with a marked increase in the parenchymal thickness and stretching and splaying of the calyces, somewhat akin to that seen in autosomal dominant cystic renal disease (adult polycystic kidneys). Non-function may be noted. US would reveal grossly enlarged kidneys with lobulated contours, marked parenchymal thickness and distortion of sinus echoes. CE-CT would reveal grossly enlarged kidneys with very little of the collecting system seen, which would be markedly distorted. Non-function may be noted. Post contrast MR would be expected to show these lesions better. It may be helpful in quantifying the residual normal parenchyma, which may be of some prognostic significance. It should be noted that cysts of various types may accompany diffuse NB, closely simulating adult polycystic kidney disease. The nephromegaly and decreased parenchymal echogenicity can also be mistaken for a lymphoma on US. However both adult polycystic and lymphoma are rather rare in infancy[24]. Massive bilateral involvement is also known as massive nephroblastomatosis[4],[25],[27]. To summarise, nephroblastomasis findings at IVU include an irregular renal contour and distortion of the collecting system. In many cases of NB the IVU is normal[1]. Sonographic changes in NB are usually very subtle, often the only sonographic changes are a subtle distortion of the sonographic architecture, or solely diffuse renal enlargement. US typically reveals hypoechoic nodules in the kidney, although the lesions may be iso or hyperechoic compared to the normal renal parenchyma[24],[28]. The presence of a nodular renal surface is a secondary sign suggestive of NB. Prenatal diagnosis of NB was made in two siblings by Ambrosino et a1[29]. The kidneys appeared uniformly enlarged and of usual echogenicity. Both cases had foci of renal calcifications. They stated that the presence of renal parenchymal calcification in homogenously enlarged kidneys may prove to be a sign suggestive of NB[29]. Occasionally NRs may be cystic[1]. US is less sensitive than CT in the diagnosis of NB[30]. Contrast enhanced CT reveals the foci of macroscopic NRs as low attenuation lesions in the kidney. Although microscopic specimens of NRs occasionally demonstrate fat, micro calcification or both, CT documentation of fat has not yet been described. A single case of calcification noted on CT was reported only recently[22]. As on IVU and US, nodularity of the surface may be noted with CT. CT is currently considered the modality of choice in the evaluation of the NW. However, even CT may fail to demonstrate NB[31]. The failure to detect NB may be because most of the plaques are thin, (a few mms) are peripherally located and may be hidden due to volume averaging[31]. Raising the suspicion of NB whenever a lobulated appearance is noted on CT and obtaining thinner sections with a narrower window on dynamic CE-CT, or preferably performing post gadolinium MR, may help in avoiding this failure. Any scalloping of the renal outline noted should not be presumed to be due to prominent fetal lobations. In fact, there is sufficient reason to believe that scalloping of the renal outline deserves special attention as a sign suggestive of NB and care should be taken to carefully scrutinise such kidneys, especially if there is reason to believe that the patient is at risk for developing NB. Kissan et al[32] had stated that persistent fetal lobations are present in the enlarged kidneys of NB, which are also the sites of perilobar NB and related lesions. Fernbach et al[30] had noted cortical scalloping on U, that was indistinguishable from prominent fetal lobations, in a child with NB, but felt that as this could be normally present, this could not be used to suggest the diagnosis of NB. Cormier et al[31] had noted small notches on CE-CT in the contralateral kidney of a child with a Wilms' tumour and had interpreted them as being due to fetal lobations. However, on inspection at surgery, multiple white sub-capsular plaques, measuring 1 to 2 cms in diameter and upto 0.5 cms in depth were noted in the regions corresponding to the notches and were proved on examination of the frozen section to be NB. On angiography the sub-capsular tissue does opacify with the nephro-gram, and thus there is a scalloped outer margin to the opacified kidney[23] [Figure:4b] gives a diagrammatic representation of the pathologic angio-graphic, US and CT basis for considering a scalloped margin, giving the appearance of prominent fetal lobations to be due to NB. The appearance of NB on MRI has been described only in two cases[22],[23]. Kangarloo et al (1986)[33] described these as areas of low intensity on T1 weighted images. Hauseger et al (1991)[22] stated that the foci of NB were well shown on Gd-DTPA enhanced T1 weighted spin echo sequence, as non-enhancing lesions, whereas the lesions were not detectable in native T1 and T2 weighted MR scans. Gylys-Morin et al[34] found the overall sensitivity of detection of NRS to be 43% on non-enhanced images and 58% when gadolinium- enhanced images were added. They found that NRS admixed with Wilms tumours less than 4 mm in diameter were not depicted at MRI. On gadolinium-enhanced T1 weighted images, they found Wilms' tumours and hyper-plastic NRS to be hypo-intense and iso or slightly hyper-intense to the renal cortex on T2-weighted images while sclerotic NRS were hypo-intensive on T2 weighted images. On all images including gadolinium-enhanced T1 weighted images they found the signal intensity of Wilms' tumours to be in-homogenous, and that of NRS to be homogenous. NB can have a broad spectrum of different fates, ranging from quiescent or obsolescent nephrogenic rests to the development of nephroblastomas[14],[22]. Since the fate of NR is not reliably predictable, each NB must be considered to be a potential precursor of a Wilms' tumour. The prevalence of NB in unilateral Wilms' tumour is 41%, in synchronous bilateral Wilms' tumour 90% and in metachronous contralateral Wilms' tumour 94%[14]. About 40% of patients with NB have bilateral disease[22],[35]. This means that, in children with unilateral Wilms' tumour, NB of the contralateral kidney has to be expected in at least 16% of cases. Therefore in all children with Wilms' tumours both kidneys have to be subjected to a very careful diagnostic work-up. Diagnostic imaging modalities play a major role in the primary diagnosis and for follow up. [Figure:5] While the NB complex is isolated, it has been often associated with certain terato-logical disorders. The best documented are the Beckwith Wiedeman syndrome[36], the Klippel - Trenaunay syndrome[37], the Drash syndrome[38] trisomy 18[39], trisomy 13[19] splenic agenesis with malformation of the liver[21] and the constellation of anomalies associated with the familial NB described by Liben et al[40] and Periman et al[41],[42]. Both Wilms' tumour and pseudohermaphroditism, two conditions linked to NB, have been shown to be, on occasion, associated with "nephron disorders" including forms of early onset nephrotic syndrome[43],[44],[45],[46],[47]. Functional renal disorders might result from the effects of regressed herediofamilial nodular renal bias-toma or even NB in the renal cortex.
The role of imaging in evaluating patients suspected of having NB, Wilms tumour, or both include: a) preoperative assessment in a patient suspected of having a Wilms' tumour b) follow-up of patients with known micro or macroscopic NB, to detect neo-plastic change and c) screening of patients with syndromes associated with NB and Wilms' tumour[1]. Since small macroscopic foci of NRs can be missed even on CT31, the conventional approach has been direct inspection of the contra-lateral kidney during surgical resection of a Wilms' tumour, even if CT findings are negative. However, contra-lateral surgical exploration is not advocated by some surgeons[48]. The contra-lateral kidney may not be sufficiently mobilised to allow a thorough evaluation of its posterior aspect, especially when surgery is performed with an incision on the side of the affected kidney[30]. Imaging also scores over direct inspection in the diagnosis of intra-lobar or peri-lobar NRs situated deep in the renal parenchyma. This would be particularly significant because of the high incidence of development of a metachronous Wilms' tumour in patients with intra-lobar NRs [Figure:5] CT should be used as the initial imaging modality in assessing the contra-lateral kidney preoperatively[1]. Imaging is vitally important in the follow-up of patients with known NB. The results of imaging studies dictate which patients should undergo biopsy or resection of suspicious lesions, the hallmark of neo-plastic transformation of a benign NR is enlargement. NRs that become rounded, expansible and mass like should be removed to rule out neo-plastic change[1]. Needle biopsy is inadvisable, since the variable histologic characteristics of NRs may result in misleadingly innocent looking specimens. Known lesions should be followed with serial examinations, careful comparisons with measurements should be made to identify lesions that are enlarging. Patients considered to be at high risk for development of Wilms' tumours are those who previously had a Wilms' tumour and in whom NB is diagnosed with imaging or biopsy, as well as patients with a de-novo diagnosis of NB. The Peri-man Syndrome[41],[42] and the Liban syndrome[40] would fall into this category. Patients in the low risk group include those with Beck-with Wiedeman syndrome[36] Drash syndrome[38], or hemi-hypertrophy and those who previously had a Wilms' tumour in whom there was no biopsy or imaging confirmation of NB. The imaging protocol for these groups as suggested by White et al[1] is given in [Table - 4] The high risk group requires (a) US every 2,3 and 4 months for the 1st, 2nd and 3rd year after diagnosis. respectively: then every 6 months for 2 years, then every year until the child is 10 years old. (b) CT every 6 months for 2 years after diagnosis then every 12 months for 3 years, then again at age 10 years. They have also suggested that the change noted with US should be confirmed with CT. Hausegger et al[22] recommend performing contrast enhanced MR studies parallel to the basic CT examination. If MR findings are consistent with CT findings, they dispense performing CT examinations in further follow-up and rely on Gd-DTPA enhanced MR studies. The low risk group would require (a) US every 4,6 and 8 months for the 1st, 2nd and 3rd-4th year after diagnosis, respectively then every year till the child is 10 years old. b) CT every 6 months for 1 year after diagnosis then every 12 months for 4 years after diagnosis and again at age 10 years. Any change noted with US should be confirmed with CT, and any low risk patient in whom NRs subsequently appear should be switched to the protocol for high risk patients. Their proposed imaging protocols are designed to balance the advantages of CT (high sensitivity) with those of US (low cost, no radiation exposure). The most intense screening is performed during the early periods following the diagnosis of Wilms' tumour or between the ages of 1 and 5 years, when the patient is al highest risk. Screening intervals take into account the fact that metachronous tumours have been reported to occur 2 to 52 months following appearance of the primary Wilms' tumour or between the ages of 1 and 5 years, when the patient is al highest risk. Screening intervals take into account the fact that metachronous tumours have been reported to occur 2 to 52 months following appearance of the primary Wilms' tumour[49]. Screening is continued only upto the age of 10 years as after that the risk of Wilms' tumour development becomes minimal[50].
US is the first diagnostic modality for detection of suspected tumours lesions of the kidneys. However, performing US as the only primary diagnostic procedure in evaluation of children with Wilms' tumour or suspected nephroblastomatosis should be avoided, since US can miss a considerable number of foci of nephroblastomatosis. Contrast enhanced CT can show the multi-focal involvement of nephroblastomatosis more accurately than either IVU or US. US may miss cortical lesions. IVU also normally reveals only the dominant mass of the Wilms' tumour. CT reveals a clear demarcation between non-enhanced nephroblastomatosis and enhanced normal renal parenchyma contrast enhanced CT is therefore recommended in the evaluation of clinically abnormal and contralateral kidneys in all children with a suspected Wilms' tumour. MR has shown great potential, however experience at this stage is limited and further studies are needed to evaluate the role of this imaging modality vis a vis nephroblastomatosis.
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4] [Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]
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