Comparative Ultrastructural Study of So-Called Renal Adenoma and Carcinoma

Vol. 108, September Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright © 1972 by The Williams & Wilkins Co.

COMPARATIVE ULTRASTRUCTURAL STUDY OF SO-CALLED RENAL ADENOMA AND CARCINOMA EDWIN R. FISHER

BRANIMIR HORVAT

AND

From the Department of Pathology, Shadyside Hospital and University of Pittsburgh, Pittsburgh, Pennsylvania

It is generally accepted that many solid adenomatous growths of the renal cortex represent small or incipient carcinomas. This view is based for the most part on the comparable age incidence of socalled adenomas and carcinomas/ their often indistinguishable histopathologic features, 2 • 3 their similar epidemiologic relationship to cigarette smoking4 and reports purporting to illustrate the malignant transformation of lesions previously regarded as benign. 5 • 6 The validity of this latter evidence is questionable since these reports lack information which excludes the possibility that the original growth was a carcinoma from the beginning or, conversely, if benign at its inception, whether it became biologically malignant. Histologic estimation of malignancy in the absence of metastases is inadequate evidence in this regard. This criticism characterizes the pathologic and clinical dilemma concerning the distinction of socalled renal adenoma and carcinoma. Bell concluded that such lesions which were less than 3 cm. in size were more aptly designated as benign, yet several smaller tumors in his series did exhibit metastases. 7 Other studies have disclosed a somewhat direct relationship between the size of such lesions and metastases. 8 Thus, prognostic evaluation of these renal neoplasms (except for the presence or absence of metastasis) appears to rest upon the somewhat arbitrary determination of tumor size. There is some consensus on the histogenesis of renal carcinoma. The work of Stoerk9 which argued Accepted for publication December 22, 1971. 1 Cabot, H. and Middleton, A. W.: Relation of socalled adenoma of kidney to carcinoma of kidney. Trans. Amer, Ass. Genito-Urin. Surg., 31: 91, 1938. 2 Willis, R. A.: Pathology of Tumours. St. Louis: C. V. Mosby Co., p. 456, 1953. 3 Evans, R. W.: Histological Appearances of Tumours With a Consideration of Their Histogenesis and Certain Aspects of Their Clinical Features and Behavior. Baltimore: The Williams & Wilkins Co., p. 662, 1956. 4 Bennington, J. L., Ferguson, B. R. and Campbell, P. B.: Epidemiologic studies of carcinoma of the kidney. II. Association of renal adenoma with smoking. Cancer, 22: 821, 1968. 6 Long, R. J., Utz, D. C. and Dockerty, M. B.: Malignant transformation of a renal adenoma: report of a case. Canad. J. Surg., 9: 266, 1966. 6 Hicks, W. K.: Benign tubular adenoma with malignant transformation. J. Urol., 71: 162, 1954. 7 Bell, E.T.: Renal Diseases. Philadelphia: Lea & Febiger, p. 428, 1950. 8 McDonald, J. R. and Priestley, J. T.: Malignant tumors of kidney; surgical and prognostic significance of tumor thrombosis of the renal vein. Surg., Gynec. & Obst., 77: 295, 1943. 9 Stoerk, 0.: Zur Histogenese der Grawtiz'schen Nierengeschwiilste. Beitr. z. path. Anat. u. z. allg. Path., 43: 393, 1908.

against the suprarenal origin of so-called clear cell carcinoma or hypernephroma of the kidney has been supplemented by electron microscopic studies that have disclosed the ultrastructural similarities of neoplastic and renal tubular cells. 10- 12 In view of these findings it was considered worthwhile to study by electron microscopy a neoplasm which, despite its histologic similarity to renal carcinoma, was designated a renal adenoma because of its small size and the absence of overt metastases and to compare this with 2 unequivocal renal carcinomas. The results provide pertinent information concerning the histogenesis of the so-called renal adenoma as well as its relationship to carcinoma. CASE REPORTS

Case 1. A 38-year-old white woman experienced

sudden onset of hematuria and pain in the upper left flank. The latter was accompanied by tenderness and a palpable mass. Excretory urography (IVP) disclosed a mass in the lower pole of the left kidney which distorted the adjacent collecting system and middle calix. The appearance of the lesion after selective left renal arteriography was strongly suggestive of renal carcinoma. X-ray examination of the chest was negative. A left nephrectomy was performed. Convalescence was uneventful and the patient is clinically free of disease 1 year postoperatively. The kidney weighed 400 gm. and contained a round, circumscribed mass of firm yellow tissue at the lower pole, measuring 7 cm. in diameter. There was no macroscopic evidence of perirenal or intravascular extension of the neoplasm. :;V[icroscopically, the lesion was an epithelial neoplasm comprised of fairly large cells with optically clear and less frequently granular cytoplasm. Nuclei were relatively small, for the most part uniform and often eccentrically placed (fig. 1). Only rare mitosis was evident. The tumor cells were arranged in tubules, solid masses or alveolated patterns, frequently separated by delicate septa of capillaries and connective tissue. Inside some secondary 10 Oberling, C., Riviere, M. and Haguenau, F.: Ultrastructure of clear cell epitheliomas of the kidney (hypernephroma or Grawitz tumor) and its implication for the histogenesis of these tumors. Bull. Ass. Franc. Cancer, 46: 356, 1959. 11 Oberling, C., Riviere, M. and Haguenau, F.: Ultrastructure of the clear cells in renal carcinomas and its importance for the demonstration of their renal origin. Nature, 186: 402, 1960. 12 Seljelid, R. tind Ericsson, J. L.: Electron microscopic observations on specializations of the cell surface in renal clear cell carcinoma. Lab. Invest., 14:

435, 1965.

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branches of the renal vein were found intraluminal tumor thrombi that contained :fibrin clot and were covered by endothelial cells. The neoplasm was circumscribed but portions of a peripelvic lymph node were noted to be replaced by neoplasm. Case 2. A 65-year-old white man was admitted to the hospital owing to weakness, fever and left flank pain. Examination disclosed tenderness as well as a palpable mass in the left flank. Microscopic hematuria was noted on repeated occasions. IVP revealed a mass in the upper pole of the kidney with caliceal distortion. A left nephrectomy was performed and the postoperative course was uneventful. However, the patient died 3 years postoperatively, apparently with clinical evidence of widespread metastases (no necropsy was obtained). The resected kidney weighed 1,000 gm. The superior pole was replaced by a :firm yellow mass measuring IO by 8 by 6 cm. This same tissue appeared as a thrombus within the lumen of a large branch of the ·1 renal vein and the mass was adherent to the perirenal adipose tissue. Microscopically, the lesion was an epithelial neoplasm comprised of optically clear and granular cells with relatively small nuclei arranged in tubules, some of which exhibited papillary invaginations, solid masses and al veolated structures. Variably thick :fibrovascular trabeculae coursed throughout the neoplasm. Occasional mitoses were noted, alFrn. 1. Case 1. Tubular area of clear cell carci- though generally the nuclei were uniform and ecnoma. Reduced from XI50. centric. Extension of the neoplasm into perirenal

Fm. 2. Case 3. A, papillary area of renal adenoma. Except for some cells which exhibit cytoplasmic vacuolation, appearance of lesion closely resembles that of more commonplace papillary tubular adenoma of kidney. B, area from renal adenoma which histologically more closely resembles areas of renal carcinoma than that depicted in A. Reduced from X 150.

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F!G. 3. A, portions of cells from renal carcinoma demonstrate replacement of much of cytoplasm with large lipid droplets (L) and glycogen particles. Reduced from X17,500. B, portions of other cells comprising renal carcinoma which contain few irregular mitochondria, vacuoles of endoplasmic reticulum and lipid droplets. Free S\lrfaces of several contain microvilli (arrow). Reduced from X12,000.

adipose tissue and large branches of the renal vein was noted. Case 3. A 65-year-old white man was admitted to the hospital for operative correction of occlusive aortic vascular disease with manifestations ch31racteristic of Leriche syndrome. During the cour~e of operation a firm yellow nodule measurjng---iwproximately 2 cm. in diameter was noted beneath. the renal capsule in the lower pole of the left kidrieJ. This was easily "shelled out". There was no evidence of other disease and the vascular defect was repaired by prosthetic graft. The patient has remained in good

health without evidence of neoplastic disease for 1 year postoperatively. The lesion measured 2 cm. in cross diameter and was comprised of homogeneous, moderately firm yellow tissue. Microscopically, in some areas the neoplasm was comprised of epithelial cells arranged in tuhq1es with papillary invaginations whose stalks were c0\):1prised of delicate fibrovascular trabeculae (fig. 2, A}, These areas resembled the small papillary adenomas not uncommonly observed in kidneys and regarded by some as universally benign. In other areas the

ULTRASTRUCTURAL STUDY OF RENAL ADENOMA AND CARCINOMA

cells were arranged in more solid aggregates without papillary invagination and they more closely resembled carcinoma (fig. 2, B). In both cell

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cytoplasm was reticulated, and occasionally it was clear or contained sparse granules. Nuclei were small, often eccentric and uniform without mitosis.

Fm. 4. Portions of cells comprising renal adenoma. Mitochondria and other organelles are sparse. Several large lipid droplets are present as are microvilli on free surfaces of cells. Appearance of these cells generally is similar to those of carcinoma depicted in figure 3, B. Reduced from X 12,500.

Fm. 5. A, apical portion of cell comprising renal adenoma demonstrates microvilli, lysosomal body (]) and small vesicles. Reduced from B, basilar portion of cell comprising renal adenoma adjacent to basement membrane of membranes and/or intercellular spaces reminiscent of proximal tubular epithelium.

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An occasional foam cell was disposed among the neoplastic cell aggregates. The lesion was circumscribed by fibrosis and compressed renal tissue. COMMENT

cytoplasmic in,clusions as well as frequent pinocytic vesicles noted in many adenoma cells, although not specific, are present in normal tubular epithelial cells. The cristae observed in mitochondria of adenoma cells were relatively thin and short and, in this respect notably distinct from those observed in cells of the adrenal cortex, in which cristal arrangement and structure are distinctive allowing for their zonal differentiation. It is significant that these ultrastructural features of the adenoma cells were evident in areas which by light microscopy resembled the carcinomas as well as in those foci resembling the more common papillary tubular adenomas which, according to some investigators, never metastasize. 2• 7 Some of these features indicating the renal tubular origin of the so-called adenoma have been recounted previously as suggestive of the tubular origin of carcinoma (clear cell carcinoma, hypernephroma, Grawitz tumor) 10- 12 and they were observed in the examples of carcinoma examined in this study. However, cellular junctional complexes, considered by some as indicative of the renal tubular origin of carcinomas, were not observed in examples of this latter or the adenoma. 12 Villous transformation of cell membranes as well as basilar infoldings was sparse in the carcinoma cells and required diligent search for their detection. Most cells comprising these neoplasms contained relatively few cytoplasmic organelles. The incidence of these latter was strikingly less in carcinoma cells than in adenoma cells. This relative simplicity of the carcinoma cells is not unique for renal carcinoma, and was also evident in rare cells of the adenoma which exhibited a benign histologic appearance as well as those areas more closely resembling carcinoma. This information suggests that cells comprising carcinoma exhibit a greater degree of cellular dedifferentiation than those of the adenoma, a feature which may be related to differences in their biologic behavior. However, the qualitative similarities suggest that the adenoma may represent an early structural stage in the development of renal carcinoma.

Electron microscopy. Portions of the neoplasms were fixed in 1 per cent osmium tetroxide, buffered with veronal, dehydrated and embedded in Marag;las. Ultrathin sections stained with lead citrate were examined with a Philips EM 200 electron microscope. Carcinoma. Cells comprising the carcinomas were generally round or polygonal. Nuclei were variable with round, ovoid and indented forms. Nuclear chromatin was evenly dispersed and one or more relatively small nucleoli was present. The cytoplasm contained relatively few ovoid mitochondria with occasional thin cristae. Short lacunae and vacuolar forms of coarse and smooth endoplasmic reticulum and variable numbers of Golgi structures were evident. Smaller pinocytic vesicles were present, particularly beneath the cell membrane in some cells. A striking feature of the cytoplasm was the presence of varying numbers of lipid droplets and glycogen particles (fig. 3). Cell membranes were for the most part simple without attachment plates. The free surface of a few neoplastic cells exhibited villi. In foci in which basement membrane was evident basilar portions of the neoplastic cells exhibited moderate infolding of plasma membranes. Adenoma. Many of the cells comprising the adenoma generally appeared similar to those of the carcinoma (fig. 4). However, there appeared to be slightly greater numbers of mitochondria, lysosomes, Golgi structures, vacuolar forms of endoplasmic reticulum and smaller pinocytic vesicles. These features were particularly evident in foci which by light microscopy exhibited a papillary configuration. However, it was often difficult if not impossible to qualitatively distinguish individual cells of these latter areas from those that comprised the more solid areas of the tumor. Cell contact was without attachment plates. Villous transformation of cell membranes was more conspicuous as were interSUMMARY cellular spaces and infolding of plasma membranes Electron microscopic study of an example of soat the basilar portions of cells than in those of the carcinomas (fig. 5). Less glycogen and lipid were called renal adenoma and 2 carcinomas, which were present in these cells than in those of the carcinomas. principally of the clear cell type, revealed microvilli, infolding of basilar plasma membranes, cytoplasmic Nuclei were round or oval with occasional nucleoli. pinocytic vesicles and lysosomes in some cells of DISCUSSION both. Further, cristal structure of mitochondria in Several ultrastructural features of the cells com- cells of the adenoma as well as carcinomas was disprising the renal adenoma are consonant with their tinct from that characterizing adrenal cortical cells. renal tubular origin rather than adrenal or other These findings indicate the renal tubular origin of derivation. Microvilli on the free surfaces of many the so-called adenoma and confirm that carcinoma cells of the adenoma appear to be analogous to the has a similar histogenesis. These ultrastructural embryonic form of brush border observed in cells features were more frequent and lipid and glycogen of the proximal convoluted tubule or other portions less conspicuous in cells comprising the adenoma of the adult nephron. Infolding of the plasma mem- than in those of the carcinomas. These different debrane of basilar portions of tumor cells adjacent to grees of cellular differentiation may be related to the basement membrane or the formation of intercellular divergent biologic behavior of these neoplasms. spaces at such sites is also suggestive of the arrange- Nevertheless, the qualitative similarities are conment of cell membranes of non-neoplastic proximal sonant with the view that regards the renal adenoma convoluted tubular epithelium. Lastly, lysosomal as a small or structurally early form of carcinoma.