—  SPECIALTY CONFERENCE  —

Pediatric Pathology

Case 3 - Nephroblastoma with Focal Anaplasia

Charles Timmons
Children's Medical Center
Dallas, TX


Click on each slide thumbnail image for an enlarged view
Clinical History
The patient, at presentation to her primary physician, was a 15-month old girl whose parents had begun noticing an increased firmness in the right side of her abdomen approximately two months prior to admission. This firmness persisted, although she had no complaints related to it and was otherwise asymptomatic. The primary physician suspected a renal tumor and referred her for further evaluation. Radiography demonstrated an approximately 8-cm discrete multicystic mass originating in the right kidney, extending across the midline and compressing the inferior vena cava. The residual right kidney was compressed and hydronephrotic. The left kidney was unremarkable. There was no abdominal lymphadenopathy. An exploratory laparotomy followed by right nephrectomy was performed.

The resected kidney weighed 462 grams and measured 12 x 10 x 8 cm. Bisection in a coronal plane (Figure 1) revealed an 8.5 x 8.0 x 6.0 cm, sharply demarcated, multiloculated cystic mass, with a discrete rim of residual renal parenchyma. The cysts ranged up to 3.5 cm in diameter. Their septa were delicate and contained no obvious expansile masses. Polypoid "tongues" of tissue composed of cysts and myxoid soft tissue projected from the main mass into the renal calyces and extended 4 cm down the ureter with mural attachment. The histology is illustrated (Figures 2-4). There was neither hilar nor capsular invasion, and a hilar lymph node was free of tumor.


Case 3 - Figure 1 - Right kidney, bisected, illustrating a well demarcated multicystic mass with extension into adjacent renal calyces. The ureter is distended by similar tissue in its lumen. (Gross appearance)
Case 3 - Figure 2 - Right kidney. The cysts are lined by mature epithelium, ranging from tall "hobnail" cells with abundant cytoplasm to flattened, inconspicuous epithelial cells. The septa, while generally fibrous or fibromyxoid, focally are populated by condensations of round or elongated immature cells forming occasional tiny tubules. Occasional aggregates of lymphocytes and plasma cells are also present. (H&E, original magnification x 100)



Case 3 - Figure 3 - Right kidney. The polypoid projections of tissue into the calyces and ureter resemble the septal tissue but with a more myxoid and edematous interstitium. A cambium layer of condensed immature cells is focally present. The lining epithelium is mature and cuboidal to flat. (H&E, original magnification x 40)
Case 3 - Figure 4 - Right kidney. In one focus of the main mass, the interstitial cells assume bizarre anaplastic features, characterized by marked cellular pleomorphism, nuclear hyperchromasia, and very large multipolar or disorganized mitotic figures. Some of the anaplastic cells show cytoplasmic hyaline globules and karyorrhexis. The anaplastic cells, while focal, tend to infiltrate along the adjacent septa rather than impinging upon the cysts. Extensive further sampling revealed no additional anaplastic foci in the mass. (H&E, original magnification x 200)


The post-operative period was uneventful, and she was discharged on day #7 of hospitalization. No chemotherapy or radiation was given. There has been no evidence of disease recurrence or metastasis, with follow-up of ten years.

Differential Diagnosis:
Wilms tumor, cystic
Cystic nephroma
Cystic partially differentiated nephroblastoma
Multicystic dysplasia of kidney
Autosomal dominant polycystic kidney disease
Mesoblastic nephroma
Metanephric stromal tumor
Renal cell carcinoma, cystic

Final Diagnosis: (Cystic Partially Differentiated) Nephroblastoma with Focal Anaplasia

Discussion Points:

1. The definition of Cystic Nephroma and Cystic Partially Differentiated Nephroblastoma as part of a spectrum of embryonal tumors of kidney:
Wilms tumor, also called nephroblastoma, is a well known and extensively studied malignant embryonal neoplasm of the kidney, characteristically composed of a mixture of immature mesenchymal elements (stroma), condensed poorly differentiated embryonal cells (blastema), and primitive epithelial elements, in widely varying proportions. While Wilms tumor may be cystic, formation of large cysts is not its typical growth pattern. [1]

Cystic nephroma, in contrast, is by definition a completely cystic lesion entirely composed of mature stromal elements and differentiated epithelium. The mature condition of its cellular components predicts the benign nature of the entity; and its former name of "multilocular cyst of the kidney" is indicative of the history of uncertainty surrounding its classification even as a neoplasm. While most cases of cystic nephroma occur in children under four years of age, with a 2:1 male predominance, a substantial minority occurs in adults over 30 years of age with an 8:1 female predominance. This striking bimodal age demography suggests underlying heterogeneity within either the entity itself or its underlying causes. [2, 3] .

Among the observations cited in favor of the neoplastic nature of cystic nephroma, at least in its pediatric manifestation, is its occasional association with nephroblastomatosis or even Wilms tumor in the ipsilateral or contralateral kidney [1], and its even rarer familial association with another embryonal tumor, the pleuropulmonary blastoma of lung [4]. Areas resembling cystic nephroma have been reported in Wilms tumors [5].



The most venerable argument in favor of the neoplastic nature of pediatric cystic nephroma has been the existence of lesions intermediate between cystic nephroma and Wilms tumor, in which the septa are populated by blastema or immature mesenchymal elements without producing a solid expansile mass. This intermediate form has been termed cystic partially differentiated nephroblastoma, and a review of the material in the National Wilms Tumor Study and personal consultation files by Joshi and Beckwith [6] crystallized the criteria for its diagnosis and distinction from either Wilms tumor or cystic nephroma. Joshi and Beckwith [6] defined cystic nephroma as follows:

  1. Cystic nephroma is composed entirely of cysts and their septa.
  2. It forms a discrete mass, well demarcated from the noncystic renal parenchyma
  3. The septa are the only solid portion, conforming to the outlines of the cysts, without solid expansile nodules
  4. The cysts are lined by flat, cuboidal or hobnail epithelium
  5. The septa are composed of fibrous tissue in which well-differentiated tubules may be present; poorly differentiated tissues are absent.
Joshi and Beckwith [6] defined cystic partially differentiated nephroblastoma as follows:
  1. Criteria identical to cystic nephroma.
  2. Criteria identical to cystic nephroma.
  3. Criteria identical to cystic nephroma.
  4. Criteria identical to cystic nephroma.
  5. The septa contain blastemal cells in any amount, with or without other embryonal stromal or epithelial cell types. This requirement for blastemal cells, as opposed to any immature elements, has subsequently been relaxed: "CPDN differs from CN only in that the septa of CN contain blastemal or other poorly differentiated cell types." [1]
The neoplastic nature of cystic partially differentiated nephroblastoma is more firmly established than that of cystic nephroma. In addition to the occurrence of Wilms tumor and cystic partially differentiated nephroblastoma in the same patient [6], several investigators have reported clonal cytogenetic abnormalities, which often overlap with those observed in other neoplasms including Wilms tumor [7, 8, 9] . A characteristic cytogenetic abnormality has not emerged, however.

Eble and Bonsib [2] have convincingly argued that the distinct epidemiology of adult and pediatric cystic nephromas warrant separate classification of the two demographic groups. However, they have also proposed that all pediatric cystic nephromas should be classified as cystic partially differentiated nephroblastomas, a suggestion which has not received general acceptance and which is not reflected in the most recent AFIP fascicle on renal tumors [1].

2. The significance of the histologic continuum between Wilms Tumor, Cystic Partially Differentiated Nephroblastoma, and Cystic Nephroma
Beckwith and Joshi [6], in conceptualizing the histologic continuum of Wilms tumor, cystic partially differentiated nephroblastoma and cystic nephroma, noted its similarity to that of neuroblastoma, ganglioneuroblastoma and ganglioneuroma. They did not, however, propose that this histologic continuum represents an actual maturational sequence as is believed to exist in the neuroblastic tumors, although the paper is sometimes misquoted as saying just that. In fact, there is as yet no convincing evidence for such a spontaneous sequence of events, and the fact that pediatric cystic nephromas and cytic partially differentiated nephroblastomas have a median age of 12-18 months [6], which is younger than that for Wilms tumor, suggests that they are not merely Wilms tumors that have undergone maturation. An alternative possibility, also unproven, is that cystic nephromas and cystic partially differentiated nephroblastomas might arise directly from nephrogenic rests [10]. Walford and Delamarre [5] and Vujanic et al. [11] interpreted their cases of juxtaposed cystic nephromas and Wilms tumors as evidence for independent tumorigenesis of Wilms tumor and cystic nephroma from nephroblastomatosis. Unfortunately, the interpretation in both reports is clouded somewhat by a history of pre-operative chemotherapy, which might have obliterated immature elements from the subsequently diagnosed cystic nephromas, a phenomenon which is well described in treated Wilms tumors [12]. This potential is the basis for the exclusion of tumors having received pre-operative chemotherapy from the diagnosis of either cystic nephroma or cystic partially differentiated nephroblastoma, according to the most recent AFIP fascicle on renal tumors [1].

3. The significance of growth into the lumen of the collecting system
Almost immediately after Joshi and Beckwith had defined the classic appearance of CPDN [6], they described eleven additional cases [13] with a variant histology, sometimes only focal, in which papillary, polypoid or nodular excrescences up to 4 cm in size grew into the lumens of the cysts; the septa remained thin. Four of the cases also exhibited what they termed "herniation" into the renal pelvis and proximal ureter, with distension but not invasion of those structures. The authors observed a subepithelial condensation of embryonal cells, which they speculated might give rise to the luminal excrescences. Most importantly, they demonstrated that these tumors behaved in all other respects like classic CPDN's; a papillonodular growth pattern was not a marker for a more aggressive tumor.

4. The significance of anaplasia and other features of malignancy in Cystic Partially Differentiated Nephroblastoma
Analysis of the clinical and histological data from the First National Wilms Tumor Study indicated that anaplasia (defined as marked cellular pleomorphism, hyperchromasia and atypical mitotic figures), which occurred in approximately 5% of cases, was the major histological indicator of prognosis in Wilms tumor [14]. Further analysis of this and subsequent data from later National Wilms Tumor Studies led to the recognition that anaplasia was primarily a marker for resistance to existing modes of chemotherapy rather than a marker of intrinsic aggressiveness of the tumor [15, 16] . This concept led to a refinement in the distinction between focal versus diffuse anaplasia and the recognition that a patient whose Wilms tumor has anaplasia that is focal and/or Stage I has a prognosis almost as good as a patient with a favorable-histology Wilms tumor [17].

Exactly what anaplasia represents at a subcellular level has been the subject of numerous investigations but has not been completely elucidated. Wilms' tumors with anaplasia are more likely to show acquisition of complex chromosomal translocations [18]. Several studies [19, 20, 21] have indicated an association between anaplasia and TP53 gene mutations, which often can be visualized by immunohistochemistry for abnormal persistence of the p53 protein within the anaplastic cells [22, 23] . In some studies, the mutations were restricted to the areas of anaplasia, suggesting that the anaplastic foci may represent clonal expansion of cells bearing TP53 gene mutations [20]. The p53 protein is a transcriptional repressor of the multidrug resistance gene MDR-1, and hence, it has been reasonably argued that loss of normal p53 function, as may occur in anaplasia, causes increased chemoresistance by this mechanism [24]. Upregulation of telomerase activity has been shown to be an adverse prognostic indicator in favorable histology Wilms tumor [25], and Yashima et al. [26], using in situ hybridization for the RNA component of telomerase, showed positivity in four tumors with focal anaplasia, two of which expressed telomerase only in the anaplastic focus.

Anaplasia in CPDN has not been well described in the literature. The defining paper of Joshi and Beckwith [6] describes one of their 18 cases as exhibiting focal anaplasia. This 12 month old male patient, who is described only in tabular format, had a stage I tumor removed by nephrectomy and received chemotherapy. He was reportedly well without recurrence at 42 months. Other reports of cystic tumors with anaplasia have been associated with features of sarcomatous transformation [3, 10, 27, 28] and are therefore not comparable. The most recent edition of the AFIP fascicle on Renal Tumors [1] specifically excludes tumors with anaplasia, along with pretreated tumors, from classification as cystic partially differentiated nephroblastoma. While the reason for active concern in dealing with such tumors is obvious, no data to support this restriction in the classification scheme is given.

5. The Distinction of Cystic Nephroma and Cystic Partially Differentiated Nephroblastoma from other entities in the differential diagnosis of cystic lesions of the kidney.
Distinction from non-neoplastic renal cystic disease: This distinction is facilitated by the existence of a fibrous pseudocapsule around cystic nephroma and cystic partially differentiated nephroblastoma, both of which thus present as an expansile mass, albeit without solid nodules within their parenchyma. Even so, extensive replacement of the kidney by cystic nephroma or cystic partially differentiated nephroblastoma, so that the pseudocapsule largely obliterates the non-neoplastic renal tissue, can simulate multicystic dysplasia of the kidney. Autosomal dominant polycystic kidney disease might also fall into the differential diagnosis in this situation, if its manifestation in the contralateral kidney is not readily apparent. In theory, multicystic dysplastic and polycystic kidneys should have spared nephrons scattered among the cysts, allowing a distinction to be made. In practice, the presence of non-dilated mature tubules within the septa of cystic nephroma and cytic partially differentiated nephroblastoma can make this distinction difficult. [2, 3]

Distinction from multicystic renal cell carcinoma: The basis of this distinction lies in the cytology of the cells lining the cysts. Whereas in cystic nephroma and cystic partially differentiated nephroblastoma, the cyst lining is formed of large eosinophilic epithelial cells of characteristic "hob-nail" morphology, in cystic renal cell carcinoma the cyst lining is of clear cells, focally forming papillae, multiple layers or solid nodules. Fortunately, the necessity of making this distinction is uncommon, since the epidemiology of multicystic renal cell carcinoma favors older males [2, 3] . Occasional cystic nephromas in adults are described as having foci of clear cells, interpreted as renal cell carcinoma. This interpretation is not without controversy, given that they are typically of low nuclear grade and have not been reported to exhibit aggressive behavior. Indeed, multicystic renal cell carcinoma itself is a controversial entity by reason of the same patterns of histology and behavior, and the distinction between it and carcinoma arising in a cystic nephroma, based on focal versus diffuse "carcinomatous" features, may be more academic than practical [3].

Distinction from cystic variants of stromal tumors of kidney: This distinction rests on the recognition of characteristic stromal cells and architectural configurations within the septal elements of the tumor. In practice, these entities, which include metanephric stromal tumor, mesoblastic nephroma, clear cell sarcoma and rhabdoid tumor, while they may have extensive cystic change, typically lack the uniformly delicate septa of cystic nephroma and cystic partially differentiated nephroblastoma and are more prone to irregular thickening and nodularity, where the diagnostic histology can be observed. [3]

6. Treatment and outcome of Cystic Nephroma and Cystic Partially Differentiated Nephroblastoma
Both cystic nephroma and cystic partially differentiated nephroblastoma are regarded as benign tumors, and surgical resection is generally adequate. The few reports of recurrence are thought to be associated with re-growth of residual tumor. There are no reported cases of metastasis and death in the pediatric population. Blakely et al. [29] analyzed data on treatment of cystic partially differentiated nephroblastoma from National Wilms Tumor Studies 3-5 and found 21 patients, 13 of whom (including two stage II and one stage 5) received chemotherapy and 9 of whom (all stage I) received surgery only. All patients had complete resection of the tumor. Both groups had 100% recurrence-free survival.

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