NODULAR

RENAL BLASTEMA,

NEPHROBLASTOV

.4’1’)SI ( S.

AND WILMS’ TUMOR Different

Points on the Same Disease

STEPHEN

N. ROUS,

MICHAEL

D. BAILIE,

DONALD THERESA JOAN

M.D. M.D.

B. KAUFMAN, B. HADDY,

C. MATTSON,

Spectrum?

M.D. M.D.

M.D.

From the Departments of Surgery (Urology), Human Development, and Pathology, Michigan State University, East Lansing, Michigan

ABSTRACT - A case of nodular renal blastema developing into nephroblastomatosis is presented. Definitions and histopathology of these entities is given, and it is suggested that they represent a developmental spectrum with natural progression to Wibns tumor.

The purpose of this article is to report a case in which nodular renal blastema appears to represent a forerunner of nephroblastomatosis. It is suggested that these entities represent a developmental spectrum with natural progression to Wilms’ tumor. Definitions

and Histopathology

Nodular renal blastema may be defined as nests (nodules) of primitive undifferentiated cells that are found just beneath the renal capsule.’ These cells are similar to the renal blastema normally seen in the developing embryo and are the cells from which glomeruli and tubules develop. Such cells are not seen in the normal term infant and when present are abnormal.’ Histologically, nodular renal blastema cells are undifferentiated with large nuclei, prominent nucleoli, finely dispersed chromatin, and very little cytoplasm (Fig. 1A and B). These characteristics are seen with the greatest clarity under electron microscopy. Nephroblastomatosis is a diffuse involvement of both kidneys with densely packed rounded and elongated clumps of immature blastema-like

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cells resembling nephroblastomas (Wilms’ tumor). These cells are small, fairly uniform in size and shape, and have scanty cytoplasm and darkly stained nuclei that are filled with chromatin. Mitoses may or may not be visible because of the dense nuclear staining. Transitional zones are seen surrounding and continuous with the clumps of blastema-like cells in which varying degrees of immature and mature epithelial elements are present (Fig. 1C and D).3 The plentiful blastema seen in nephroblastomatosis with some few immature glomerular and tubular elements does in fact resemble and might even be called nephroblastoma (Wilms’ tumor); however, the universal involvement of‘ both kidneys and the intimate mixture of these elements with normal-looking renal tissue are not typical of nephroblastomas (Wilms’ tumor). Wilms’ tumor is histologically characterized by tubules lined with columnar epithelium and scattered through a loose connective tissue stroma. However, the microscopic picture is extremely variable because of the difference in prominence of one or the other of the basic

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FIGURE 1.llTaken from open renal biopsy. (A) Low-power and (B) high-power views showing subcapsular nodules of renal blastema. (C) Low-power and (D) high-power views showing nephroblastomatosis; note diffuse renal cortical involvement with clumps o_f blastema-like cells in which vaqing degrees of immature and mature epithelial elements are also seen.

elements of the tumor (epithelial and mesenchymal) and in the degree of differentiation reached by each. It should be .noted that the nonepithehal stroma is as complex as the epithelial components and can actually undergo metaplastic change to cartilage, bone, adipose tissue, and muscle. These elements, if searched for, are present in about half of the cases of Wilms’ tumors.4’5 Case Report A female infant of thirty-five weeks’ gestation, weighing 5 pounds, 2 ounces and having a normal karyotype, had a left hemihypertrophy at birth. Both kidneys were enlarged and readily palpable; and excretory urography failed to visualize either kidney although good concentration was present in the bladder and the blood urea nitrogen and creatinine levels were normal At four days of age, bilateral retrograde ureteropyelograms showed large kidneys with

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essentially normal collecting systems but with a suggestion of small cystlike lesions in the peripheral parenchyma of the left kidney (Fig. 2A). Additionally, a patent ductus arteriosus, a patent foramen ovale, and a macroglossia on the left side were present. Excretory urograms at three months of age had the same appearance as the retrograde studies; and in view of the unsettled question of cystic lesions in the left kidney and the possibility of infantile polycystic disease, open left renal biopsy was carried out at three and one half months of age, and the diagnosis of nodular renal blastema was made at that time. The infant was followed up carefully with serial excretory urograms which at six months of age showed no change but at twelve months of age revealed bilaterally deformed collecting systems, worse on the left (Fig. 2B). Each kidney was readily palpable at this time. Selective renal angiograms disclosed multiple filling defects

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FIGURE 2. (A) hft retrograde ureteropyelogram of four-day-old child; renal collecting system is grossly normal, but there is suggestion of some cystic lesions in upper, outer cortex. (B) At one year of age excretory urogram shows bilaterally deformed intrarenal architecture, worse on left. (C) Left selective renal angiogram done at one year of age disclosing multiple filling defects and calyceal splaying and deformity. (D) Right selective renal angiogram done at same time as (C) showing essentially same pathology as left side but perhaps not as extensive. Based on these x-ray studies diagnosis of bilateral Wilms’ tumor was made.

FIGURE 3. Selective renal angiograms after six months of chemotherapy. (A) Left kidney shows marked improvement; (B) right kidney shows similar considerable improvement in intrarenal architecture. At this stage kidneys were roentgenographically approximately 1.5 cm. smaller than in Figure 2C and D.

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FIGURE 4. Photographs taken when child was twenty-seven months of age and had been on chemotherapy for thirteen months. (A) Excretory urogram is virtually normal. (B) Left hemihypertrophy present since birth. (C) Photomicrograph from open renal biopsy shows normal renal parenchyma except fin- small subcapsular cortic :a1 nest of primitive-appearing tubules, : also noted are laminated calcijed bodies in some of tubulelike structures.

bilaterally with elongation, splaying, and deformity of the calyces, and a presumptive diagnosis of bilateral Wilms’ tumor was made on this basis (Fig. 2C and D). Bilateral open renal biopsies were obtained. The kidneys were grossly enlarged and nodular over their entire surfaces, and biopsies were taken from these nodular areas. Bilateral nephroblastomatosis with the presence of numerous mitotic figures was diagnosed from each of the biopsy sites. Since this condition was considered potentially malignant, chemotherapy with dactinomycin and vincristine was started.6 The child was given 15 pg. her kilogram of dactinomycin intravenously daily for five days, and this course of therapy was repeated again at six weeks and every three months thereafter. Vincristine 1.5 mg. per square meter of body area was given intravenously on the first and last day of each series of dactinomycin injections.

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Within three months the kidneys were no longer palpable. The excretory urograms and bilateral selective renal angiograms six months after the start of therapy showed marked improvement (Fig. 3). Roentgenographically, each kidney was about 1.5 cm. smaller than prior to the chemotherapy, and the patient was clinically thriving and well. At twenty-seven months of age, after the child had been on chemotherapy for thirteen months, excretory urograms were virtually normal (Fig. 4A). No renal angiograms were done at that time. The child weighed 42 pounds, and the left hemihypertrophy, present since birth, persisted (Fig. 4B). A third open renal biopsy was carried out, and at this time both kidneys were grossly entirely normal. Two wedge biopsy specimens were obtained from each kidney and all were histologically identical. Biopsy report showed normal renal parenchma

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except for small subcapsular cortical nests of primitive-appearing tubules and some infantile glomeruli. No mitotic figures were seen (Fig. 4C). Additionally, laminated calcified bodies were seen in some of the tubule-like structures and were thought possibly to be associated with the healing process. Comment Wilms’ tumors are generally considered to arise from the same primitive renal blastema cells as seen in nodular renal blastema. The exact relationship of nodular renal blastema to Wilms’ tumor, however, is not known since to our knowledge the former has never before been diagnosed in a living subject. What is known is that the primitive undifferentiated cells of nodular renal blastema are cytologically indistinguishable from some of the elements seen in Wilms’ tumor. Further, it has been observed that in a series of 46 autopsied patients with Wilms’ tumor, 8 patients were found to have a coexisting nodular renal blastema. In the same autopsy study, 8 other patients found to have nodular renal blastema also had multiple associated congenital anomalies from which death resulted.’ The connection of the two entities was first brought to light in this series, but whether it was coincidental or not was unknown. No follow-up study of patients found to have nodular renal blastema has heretofore been possible. According to Pottel-2 nephrogenic blastema is thought to be the origin of Wilms’ tumor, and this blastema is considered to be bipotential in that it is able to differentiate into both the epithelial and the mesenchymal tissues. Wihns’ tumor is thought to develop from the proliferation of this blastema in the absence of normal stimulation from the metanephric ducts that would ordinarily produce differentiation into tubules and glomeruli by the thirty-fourth week of gestation, and blastema cells, therefore, are never normal after a full-term birth. Potter’ believes that all such tumors (Wilms’ tumors) are therefore probably congenital. The relationship of nodular renal blastema and nephroblastomatosis may be summarized as follows: the blastema-like cells are the same; the difference between these two entities is a matter of degree with nephroblastomatosis being vastly more extensive than nodular renal blastema. It can also be interpreted that nodular renal blastema represents the focal developmen-

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tal arrest of renal tissue and nephroblastomatosis represents neoplastic proliferation of these localized malformations.7 What is the relationship of nephroblastomatosis to Wilms’ tumor? Nephroblastomatosis is more homogeneous in that it only has one primitive cell line (epithelial). It could therefore be considered a “forme fruste” of Wilms’ tumor since it has the appearance of one but not all of the manifestations of Wilms’ tumors. Nephroblastomatosis is lacking the mesenchymal (sarcoma) element of Wilms’ tumor which is not, however, always seen in all Wilms’ tumors. Although some pathologists might be inclined to consider nephroblastomatosis the same as Wilms tumor, it is probable that a greater number would call it a separate entity. The question then arises as to whether or not nephroblastomatosis develops into Wilms’ tumor. No direct proof of this is available, but in the presence of significant mitotic activity a malignant potential is suggested. Such mitotic activity was actually seen on the biopsy of the nephroblastomatosis. Moreover, the action of dactinomycin which is thought to be one of blocking ribonucleic acid prodllction, disorganizing and disrupting the cell and thereb) preventing protein synthesis, produces rapid shrinkage of a rapidly dividing lesion with significant mitotic activity. Vincristine, which is thought to destroy the mitotic spindle to produce mitotic arrest, also probably has a much greater effect on rapidly dividing cells than on more slowly dividing cells. Presumptive evidence that nodular renal blastema, nephroblastomatosis, and Wilms’ tumor are but different points 011 the same disease spectrum has been presented by the case described in which an infant “progressed” through the first two of these entities and particularly by the action of dactinomycin on nephroblastomatosis which apparently produced a rapid shrinkage of the lesion. It is possible that the natural history of nodular renal blastema stops at nephroblastomatosis and then regresses spontaneously.’ However, the dramatic change in the lesion, roentgenologically, grossly, and histologically, makes it far likelier that the nephroblastomatosis is illdeed premalignant and would have progressed to Wilms’ tumor and only regressed because of the vigorous use of chelllotherape~ltic agents which generally act most favorably on rapidly growing tissue with much mitotic activit)..

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Summary The definitions, known relationships, and basic histopathologic comparisons of nodular renal blastema, nephroblastomatosis, and Wilms’ tumor have been presented. The great histologic similarity of nephroblastomatosis to Wilms’ tumor has been shown. This histologic similarity, the numerous mitoses present in the biopsy, and the action of the chemotherapeutic agents on the nephroblastomatosis all suggest its malignant potential and its very close relationship to Wilms’ tumor. A case documenting the progression from nodular renal blastema to nephroblastomatosis has been presented. This lesion then was seen to regress to small subcapsular nests of primitive-appearing tubules after thirteen months of chemotherapy. It is suggested that nodular renal blastema, nephroblastomatosis, and Wilms’ tumor are indeed but different points on the same disease spectrum. The role of radiation therapy in nephroblastomatosis would appear to be of questionable necessity. The question ultimately arises about

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what its role Wilms’ tumor.

should

be in the

treatment

of

Department of Urology Medical University of South Carolina Charleston, South Carolina 29401 (DR. ROUS) References Nodular renal blastema. Definition and possible significance, Cancer 24: 323 (1969). 2. POTTER, E. L.: Pathology of the Fetus and Infant, 2nd ed., Chicago, Year Book Medical Publishers, 1981, 1. BOVE, K. E., et al.:

p. 199.

and HOLMAN, R. I.: Bilateral nephroblastomatosis in a premature infant, J. Pathol. Bacterial. 82: 249 (1961). solid, FOWLER, M .: Differentiated nephroblastoma: cystic or mixed, J. Pathol. 105: 215 (1971). TREMBLAY,M .: Ultrastructure of a Wilms’ tumor and myogenesis, ibid. 105: 269 (1971). MANKAD,V. N., et al. : Bilateral nephroblastomatosis and Klippel-Trenaunay syndrome, Cancer 33: 1462 (1974). LIBAN, E., and KOZENITZKY, I. L.: Metanephric hamartomas and nephroblastomatosis in siblings, ibid. 25: 885 (1970).

3. HOW, L. T.,

4. 5. 6.

7.

UROLOGY / DECEMBER 1976 / VOLUME VIII, NUMBER 6

Nodular renal blastema, nephroblastomatosis, and Wilms' tumor. Different points on the same disease spectrum?

NODULAR RENAL BLASTEMA, NEPHROBLASTOV .4’1’)SI ( S. AND WILMS’ TUMOR Different Points on the Same Disease STEPHEN N. ROUS, MICHAEL D. BAILIE,...
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