Kidney Tumors

KIDNEY A

CLINICAL AND

p ATHOLOGICAL

TUMORS

STUDY' WITH SPECIAL REFERENCE TO THE

''HYPERNEPHROID'' TUMOR

CAPT. NORMAN A. HARVEY, MC, AUS

The field of malignant kidney tumors is unique in the extension of its sphere to include so many branches of medicine. Indeed, this field is related not only to urology, roentgenology, pathology, surgery, and internal medicine, but also biochemistry, physiology, embryology, and tumor histogenesis. An attempt is made to review the literature briefly in order to show the more significant past and present trends of opinion in this subject.* Clinical and pathological data on 50 malignant renal tumors and 8 incidental "hypernephroid" tumors are presented. While the series is small, the low general incidence of kidney tumor makes a larger series feasible only in specialized clinics of large medical centers. This study is offered as perhaps a typical experience with these tumors of an average genito-urinary service in a moderately-sized (600 beds) general hospital. REVIEW

In 1883, Grawitz1 challenged the renal theory of origin asserted by earlier workers and touched off a dispute famous in the annals of medical polemics when he proposed that the common yellowish fatty kidney tumors, because of certain morphological similarities to adrenal tissue, probably originated from adrenal rests. For a time this novel hypothesis was in rather general favor 2 and its slogan the term "hypernephroma" was suggested by Birch-Hirshfeld3 in 1898. Dissenting voices were soon raised, however, and alternate proposals were made in the years that followed. 4 • 5 The first systematic refutation of the adrenal theory appeared in 1908 when Stoerk6 attacked it point by point and concluded that the renal theory was more tenable.

* For more detailed reviews of the literature, see Refs. 2, 8, and 12. Grawitz, P.: Die sogenannten Lipome der Niere. Arch. f. path. Anat. u. f. klin. Med.,' 93: 39, 1883. (Cited by Gilbert.) 2 Ewing, J.: Tumors of the Kidney, in Neoplastic Diseases, ed. 3, p. 781, 1928, ed. 4, p. 799, 1941, W. B. Saunders Co. Philadelphia and London. a Birch-Hirschfeld, F. V.: Beitriige zur pathologischen Anatomie der Nierengeschwiilste. Beitr. z. path. Anat. u. z. allg. Path., 24: 343, 1898. (Cited by Creevy.) 4 DePaoli, E.: Beitr. z. path. Anat. und z. allg. Path., 8: 140, 1890. (Cited by Bracken.) 6 Sudeck, P.: Ueber die Struktur der Nierenadenome. Ihre Stellung zu den Strumae suprarenales aberratae. (Grawitz) Arch. f. path. Anat. u. Physio. u. f. klin. Med., 133: 405, 1893. (Cited by Gilbert.) & Stoerck, 0.: Zur Histogenese der Grawitz'schen Nierengeschwuelste. Beitr. z. path. Anat., 43: 393, 1908. (Cited by Gilbert.) 1

669

670

NORMAN A. HARVEY

As Schiller 7 has pointed out, Grawitz and Stoerk employed only simple morphological criteria in support of their arguments. In later years, however, the problem has evolved into a complex one, in which biochemical, physiologic and embryologic criteria are used. 7 • 8 At the present time the renal theory of origin is the most widely accepted for the majority of kidney tumors and its proponents are also concerned with the role the renal adenoma plays in this origin. It is relevant to trace briefly the development of the latter idea. Earlier workers had differentiated the solitary adenoma from the multiple arterio-sclerotic type 9 and had further distinguished the alveolar, papillary and tubular varieties of the single growth. 10 • 11 Weichselbaum and Greenish10 also described secondary changes of fatty degeneration, cavernous blood vessels and pigmentation occurring in some of these adenomas. Sudeck,5 in 1893, held that the alveolar and papllary tumors are essentially the same and suggested that most hypernephromas are in reality renal adenomas. Lubarsch12 classified the "hypernephroid" tumors and recognized a papillary adenoma, hypernephroid adenoma, hypernephroid carcinoma, and true hypernephroma. Zehbe13 distinguished 2 groups of adenomas, 1) those with large clear cells in papillary and adenomatous arrangement, an 2) those with small granular cells in papillary arrangement. The work of several more recent investigators is of interest in this connection. Arkin 14 felt that there were 2 types of hypernephroma, one a well-encapsulated benign form which in a small percentage of cases degenerated into a second type, the malignant hypernephroma. Gottesman, Perla, and Elson 15 reported 16 incidental hypernephromas in an autopsy series of 44 cases which closely resembled the symptomatic variety both grossly and microscopically. In some malignant tumors they found all gradations from the benign form to the highly malignant appearing carcinoma. They believed that all stages in the life cycle of hypernephroma may co-exist in one tumor, and that these tumors may grow for many years. In a series of 149 tumors of the "adenoma-carcinoma" group, Bell16 was Schiller, W.: Histogenesis of so-called Grawitz tumor. Arch. Path., 33: 879, 1942. Gilbert, J.B. : Diagnosis and treatment of malignant renal tumors; historical data. J. Urol., 39: 223, 1938. 9 Sturm, P.: Arch f. Heilk., 16: 193, 1875. (Cited by Ewing.) 10 Weichselbaum, A. and Greenish, R. W.: Med. Jahrb., p. 213, 1883, Wien. (Cited by Lubarsch.) 11 Ricker: Zentralbl. f. Path., 8: 11, (Cited by Lubarsch.) 12 Lubarsch, 0., and Fahr, T.: In Henke and Lubarsch, Handbuch der Speziellen pathologischen Anatomie und Histologie, chap. 8, v. 6, 1925, Julius Springer, Berlin. 13 Zehbe: Virchow's Arch. f. path. Anat., 201: 150, 1910 (Cited by Ewing.) 14 Arkin, A.: Calcified hypernephroma of the kidney. Surg., Gynec. & Obst., 43: 155, 1926. 16 Gottesman, J., Perla, D . and Elson, J.: Pathogenesis of hypernephroma. Arch. Surg., 24: 722, 1931. 14 Bell, E . T .: Classification of renal tumors with observations on frequency of various types. J. Urol., 39: 238, 1938. 7

8

KIDNEY TUMORS

671

unable to distinguish histologically between the small non-metastasizing growths and the larger obviously malignant ones, and believes that the small tumors are the early stages or prototypes of the larger malignancies. The most frequent histological findings in both tumors were clear cells arranged in solid cords, papillary cysts or tubules, but some tumors consisted partly or entirely of dark cells arranged in similar patterns. Kozoll and Kirshbaum, 17 on the other hand, recognize a benign form, or "hypernephroid adenoma", which was a casual finding in 33 out of 77 necropsies. Like Bell, they found similar cell patterns in both the benign and malignant forms and feel that the microscopic picture is no certain criterion of benignancy since well differentiated tumors have given rise to distant metastases. However, in the absence of metastases at autopsy, given a well differentiated tumor that shows no invasion of the capsule or the adjoining renal parenchyma, and no tumor thrombi in the arcuate veins near the cortex, they feel that the classification "benign" is justified. They further believe that such tumors are potentially malignant. Stirling18 described one of the first actual transitions between a benign and malignant adenoma (cystadenoma) in 1927. Buckley19 has lately described a malignant change in a previously benign tubular adenoma. Judd and Grier20 reported a case of multiple malignant adenoma and stressed the resemblance of the larger adenomas to the adenocarcinoma or hypernephroma. Ewing2 , Creevy 21 and others have held that the transition from benign to malignant adenoma is common. MATERIAL

Fifty malignant kidney tumors and eight incidental "hypernephroid" tumors were found in the course of 4,529 necropsies and 39,857 surgical operations at the Rhode Island Hospital from 1929 through 1944. Thirty-nine of these were surgical specimens while the remaining nineteen were removed at necropsy (table 1). INCIDENCE

Renal tumors constitute about 2 per cent of all tumors in adults and about 20 per cent of those in children. 8 In this seri~ there was a 66 per cent incidence of adenocarcinoma of the cortex, 26 per cent carcinoma of the pelvis (including one epidermoid carcinoma), 17 Kozoll, D . D . and Kirshbaum, J . D. : Relationship of benign and malignant hypernephroid tumors of kidney. J. Urol., 44: 435, 1940. 18 Stirling, W. C . : Primary malignant papillary cyst-adenoma of kidney with fungating growth in pelvis . J . Urol., 17: 165, 1927. 19 Buckley, W. : Malignant transformation in previously benign tubular adenoma. Brit . J. Surg., 32: 315, 1944. 20 Judd, E. S. and Grier, J.P.: Multiple malignant adenomas of kidney. Arch. Surg. 20: 240, 1930. 21 Creevy, C. D.: Adenoma of kidney. Report of case with discussion of its relationship to carcinoma (hypernephroma). Am . J. Cancer, (supp.) 15: 2309, 1931.

I

J

672

NORMAN A. HARVEY

6 per cent Wilms tumor and 2 per cent unclassified* (table 1). In 642 cases, Priestley22 reports a 78 per cent incidence of carcinoma of the cortex, 9.6 per cent carcinoma of the pelvis, 5.7 per cent Wilms tumor, and 1.4 per cent unclassified. Other workers23 • 24 • 25 report adenocarcinomas (i.e. all malignant epithelial tumors of the cortex) in 70 to 88 per cent of renal malignancies, and pelvic carcinoma in 6 to 11 per cent. 23 , 24 There was one squamous cell carcinoma of the pelvis in this series. This is a relatively rare, highly malignant tumor, and occurs in about 17 per cent of renal pelvic tumors.26 Bell16 found none in 30,000 necropsies, and Davidson27 could glean only 87 such tumors from the literature up to 1940 and added 10 cases of his own. AGE AND SEX

The age distribution of 54 cortical and pelvic tumors is shown (table 2, fig. 1). The same heavy concentration of cases in the fifth, sixth and seventh decades TABLE

!.-Incidence of different types of malignant kidney tumor NEC.

SURG.

TOTAL

%

66 26 6 2 100

Adenocarcinoma of cortex ..... . . . .... Carcinoma of pelvis .... . ... . . .. . . . . . . Wilm's tumor ..... . . . .. . .. . .. . ... . .. . Unclassified .. .. . .. . .... . . . .. . .... . .. .

7 3 1 0

26 2 1

33 13 3 1

Total .......... . .. .. . . . . .. . . . . . ....

11

39

50

10

(81.5 per cent) is seen here that has been reported elsewhere.28 • 29 , 30 The low incidence (3.6 per cent) under 40 years of age is an agreement with Bixler et al.28 who found 6 per cent of their cases in this age group and with Bell16 who reports no renal tumors in the second and third decades in 30,000 autopsies. The spread of our cases was from 9 years to 86 years. The average age of the 54 cases was 57 .4 years and there was a slightly higher figure for the pelvic * Inclusion of the eight incidental tumors gives an incidence of 71 % hypernephroid tumors. 22 Priestley, J. T.: Survival following removal of malignant renal neoplasms. J. A. M .A., 113: 902, 1939. 23 Soloway, H. M.: Renal tumors; review of 130 cases. J. Urol., 40: 477, 1938. 24 Hyman, A.: Malignant tumors of kidney. Urol. and Cutan. Rev ., 40: 658, 1936. 25 Cahill, G. F. and Meli cow, M. M . : Calcificat ion of renal tumors and its relation to prognosis. J . Urol., 39: 276, 1938. 26 Kutzmann, A. A.: Squamous cell carcinoma of renal pelvis with special consideration as to etiology. J. Urol., 39: 487, 1938. 27 Davidson, 0. W.: Squamous cell carcinoma of renal pelvis. J. Urol., 47: 348, 1942. 28 Bixler, L . C., Stenstrom, K . W. and Creevy, C. D . : Malignant tumors of kidney; review of 117 cases. Radiology, 42: 329, 1944. 29 Melicow, M. M.: Classification of renal neoplasms: Clinical and pathological study based on 199 cases . J. Urol., 51: 333, 1944. 3 °Fowler, H . A.: Renal neoplasm, clinical study. J. Urol., 40: 581, 1938.

673

KIDNEY TUMORS

carcinoma. Comparison of the sexes showed that the average age for males was almost ten years greater than that of females (table 3). Seventy per cent of the cases were in males, a ration of 2.4: 1 (table 3). Priestley22 found 69.9 per cent males in his large series and others report a male preponderance of from 63 per cent to 84 per cent. TABLE

2.-Age distribution by decades of 54 renal tumors* NUMBER OF CASES

DECADES

1-10 11-20 21-30 .31-40 41-50 51-60 61-70 71-80 81-90 91-100

PERCENT

It

1.8

0

0

0

0 24.1 24.1 33.3 11.0 3.7 0

It

1.8

13 13

18 6 2

0 54

Total. ........................

* Includes 8 incidental hypernephroid tumors.

t Malignant cortical tumor.

100 Does not include Wilm's tumor.

SOl--l---l--+----t--+---1--1---+--+---l 70f---l---!---l--+--+---+--+--+---t--l ~

~0>--+--+---+--+---11----¼---l--+--+---I ~ u oo>--+--+---+--+---11----+---1--+--+---1 ~ ..i

40>--+--+---+--+---11----¼---1--+--+---I

~

~

so

e 201.---1----1---+-~

~

10 f---1---1----11--

Decades

10

20

:,o

-40

50

,o

70

ao

qo

FIG. 1

The same sex ratio was observed for pelvic carcinoma in our series. This is in approximate agreement with Kimball and Ferris31 who observed 74 per cent males in a series of 74 tumors of the renal pelvis. 31 Kimball, F. N. and Ferris, H. W.: Papillomatous tumor of renal pelvis associated with similar tumors of ureter and bladder; review of literature and report of 2 cases. J. Urol., 31: 257, 1934.

-· '

-

'

~

.......

674

NORMAN A. HARVEY SIZE AND LOCATION

Eight of the 15 cortical tumors found at necropsy were incidental hypernephroid growths. They varied in size from 0.3 cm. to 8.5 cm. in diameter, averaging 2.5 cm. across. The 33 cortical tumors, all obvious malignancies, ranged from 2.3 cm. to 30 cm. in diameter, averaging 11 cm. The site of origin of the cortical tumor was frequently obscured by extensive kidney involvement. In those cases in which the tumor was well delineated there appeared to be a predilection for the upper pole and there were a few more cases on the left side than on the right (table 4). Smith and Young 32 also found the upper pole favored and more cases on the left side. However, Judd and Hand, 33 while again noting a slight preference for the left kidney, found more tumors originating in the lower pole by a 6:5 ratio. Kozoll and Kirsbbaum17 observed that the right and left side were involved equally and remarked that TABLE

3.-A ge and sex distribution in 54 pelvic and cortical tumors FEMALES

MALES

AVERAGE

yrs.

Cortical tumor* ... . . . ... . .. .. .... . .. ... . Carcinoma of pelvis . .. .. .. . . . .......... . Average age (yrs .) . . .. . . .. . ...... .. . . ... . Ratio . . . ... . ... ... . . . .. .. . .... .. .. . . . .. .

29

12 4 49 .2 1

9

58 .1 2.4

56 .5 61.8 57.4

* Includes the eight incidental hypernephroid tumors. TABLE

4.-Location of 41 cortical tumors of the kidney* RIGHT KIDNEY

LEFT KIDNEY

TOTAL

PERCENT

40

Upper pole . .......... . . .. ... . .. . . .. . . Lower pole . .. ... ...... . ... . ... . . ... . . Undetermined .. .... . .. . ...... . .... .. .

8

8

16

4

3

7

17

6

12

18

43

Total. . . .... . ... .. .... .. . . .. .. . .. . .

18

23

41

100

* Includes the eight incidental hypernephroid tumors.

the lower pole was the most frequent original site on the right, while the upper pole was favored on the left. In view of such contradictory reports and since the original location is often illegible, it does not appear that priority can be assigned to any particular site or to either kidney. SYMPTOMS

The clinical manifestations of malignant renal tumor are protean and bizarre, presenting symptoms due to metastases are notoriously frequent. CreeVY34 has said that "malignant renal tumor should be classed with syphilis and tuber32 Smith, E . and Young, A.: Kidney tumors (analysis of series of 118 cases) . Canad . M . A. J., 44: 149, 1941. 33 Judd, E . S. and Hand, J . R.: Hypernephroma . J. Urol ., 22: 10, 1929. 34 Creevy, C. D.: Confusing clinical manifestations of malignant renal neoplasms. Arch. Int . Med., 55: 895, 1935.

675

KIDNEY TUMORS

culosis as among the great mimics encountered in clinical medicine." He reports that in 38 out of 92 cases renal tumor metastases simulated a variety of conditions such as primary bone tumors, pulmonary disease, portal cirrhosis, brain tumor, and carcinoma of the stomach. Likewise, Ostrum and Fetter35 collected 21 far advanced "silent" nephromata in whom other structures were first suspected. Among the erroneous diagnoses made were pulmonary tuberculosis, malignancy of the gastro-intestinal tract, acute arthritis, empyema of the gall bladder, acute cystitis and intercostal neuritis, in that order of frequency . Hematuria was present in only 3 out of the 21 cases, and the remaining 18 showed no gross or microscopic blood in the urine. In our series of necropsy cases 2 presented initial symptoms of cord tumor, for which one was subjected to an exploratory operation; 2 began with cough and 1 of these was sent to a sanatorium for suspected pulmonary tuberculosis; 1 first noticed metastatic lumps on the ribs, and another was initiated with swelling of the ankles, penis and scrotum due to tumor thrombosis in the inferior vena cava. Vaginal spotTABLE

5.- Incidence of symptoms in thirty-three adenocarcinomas of the cortex NECROPSY SE1UES

sYMPrm.rs

SURGICAL SERIES

Initial or early

Late

%

%

%

%

33 20 7 20 27 20 67

0 0 33 47 20 27 20

33 20 40 67 47 47 87

73 69 27 40 40 23 0

Total

Initial or early

-- -- -- - Hematuria ... . ....... . . . .. .. Pain ... .. . . .......... . . .. .. . Tumor ............ . . .. ..... . Systemic . . .. . .. . . . .... . . . ... Urinary . . .. . . . ........ . . . ... Gastro-intestinal. . .......... Metastatic . .......... . ... . ..

Late

Total

COMBINED SERIES

Initial or early

Late

Total

-- -- -- -- - %

%

%

%

%

0 8 19 15

73

59 51 20 32 34 22 24

0 5 24 27 15 15

59 56

·11

8 4

77 46 55 51 31 4

10

44

59 49 37 34

ting has been reported on several occasions as the presenting symptom,24 , 35 and one observer cites a case in which epistaxis due to nasal bone metastases was the inaugurating feature. 37 The literature contains many more similar instances. Apparently the peculiar metastasizing propensities of this tumor, plus the all too frequent "silent" nature of the primary tumor, combine to make it one of the most treacherous types of carcinoma. In table 5, the relative scarcity of symptoms due to the primary tumor in the autopsy group is contrasted with their relative abundance in the operative series. Contrariwise, the most common initial or early symptoms in the postmortem series were those due to metastatic deposits while the surgical series had none. Creevy34 reports initial metastatic symptoms in 56 per cent of an autopsy series and 32.6 per cent of a clinical series. s, Ostrum, H. W. and Fetter, J. S.: Silent nephroma. J. Urol., 43: 39, 1940. 36 Sharnoff, J. G. and Sala, A. M.: Vaginal metastases from hypernephroma; report of 4 cases. Am. J. Cancer, 28: 20, 1936. 37 O'Conor, V. J.: Treatment of malignant tum.ors of adult kidney. South. M. J., 34: 29, 1941.

676

NORMAN A. HARVEY

The "classic" triad of hematuria, pain and mass was present in 17 per cent of our cases. Other workers also report it less frequently than was formerly thought.23 • 28 Although we did not observe that a reversal of the symptom triad, i.e., with mass appearing first, was more frequent in the non-surgical group, Melicow29 stresses this finding in his series. HEMATURIA

The incidence of episodic grossly bloody urine in adenocarcinoma of the kidney varies from 13 per cent in 1 series,17 to 86 per cent in another,38 while most figures are between 60 and 65 per cent. It seems generally agreed that hematuria occurs with greater frequency in carcinoma of the renal pelvis, most reprorts ranging from 90 to 100 per cent39 (table 6). The most frequent mechanism of hematuria is probably by actual tumor invasion of the renal pelvis or calyces, while another possible cause is congestion of the pelvic vessels due to tumor pressure. 40 Since the tumor often originates relatively far from the pelvis and often has a capsule, it is apparent that "hematuria may be early clinically and late pathologically".28 TABLE

6.-Incidence of symptoms in thirteen carcinomas of the pelvis SYMPTOMS

Hematuria

Pain

Mass

Systemic

Urinary

%

%

%

%

%

Initial or early . ... . .... . . . . . ... .... . . . . Late . ... .. ...... .. . . ... . .. .. . .. ..... .. .

70 20

60 10

15 23

50 8

15 8

Total. ................... . ... . . . . . ....

90

70

38

58

23

Hematuria is typically an initial or early symptom, painless, fleeting and often appears in an otherwise apparently healthy person, antedating later symptoms and signs by months or even years. Obviously, such an occurrence in any person, particularly in the susceptible age group, should not be dismissed as "functional bleeding" after a negative cystoscopic examination but calls for a thorough and, if necessary, repeated investigation of the upper urinary tract. While the painless early type of bleeding is frequent, it is by no means the rule, for pain is often a concurrent symptom. This combination was seen in 40 per cent of our cases. In a significant number of cases (30-35 per cent) hematuria does not occur at all, and therefore its absence is not to be construed as weighing heavily against a diagnosis of renal tumor. PAIN

Pain, the second of the classic triad, is often the initial symptom, and has a total incidence almost that of hematuria, reports varying from 40 to 80 per 38 Fetter, T. R.: Renal carcinoma; studyof95 cases, with follow-up notes on 36. J. A.M. A., 110: 190, 1938. 39 Waters, C. A.: Preoperative irradiation of cortical renal tumors. Am. J. Roentgenol., 33: 149, 1935. 40 LeComte, R. M.: Clinical approach to cortical renal neoplasms. J. Urol., 49: 224, 1943.

KIDNEY TUMORS

677

cent. One observer,41 in a purely surgical series, found pain to be the presenting symptom more often than hematuria, and other workers17 observed a much higher total incidence of pain than hematuria in a necropsy series. It is best to consider pain according to whether its source is the involved kidney or secondary growths, and so it is classified into primary or secondary pain. Primary pain is most frequently a dull ache in the back or flank. Le Comte 40 believes that this is caused by slowly increased stretching of the kidney capsule ·or pelvis, or to slight transient urostasis, and that the dragging sensation often felt by these patients is due to tension imparted to the pedicle by the displaced organ. The occasional occurrence of considerable degrees of hydronephrosis would also be a contributing factor. A less frequent manifestation of primary pain, one which occurred twice in our series, is the sharp, lancinating type, usually associated with renal or ureteral stones. Both of our cases were pelvic carcinomas with renal stones. In 1 case there was a colicky pain with typical ureteral radiation, while in the other there was a knife-like pain in the kidney region which radiated to the ipsilateral shoulder. Other workers24 • 40 , 42 assert that the passage of clots and bits of tumor tissue may also incite attacks of colic. We found that hematuria was often associated with pain but not of the colicky type. Another possibility is that the small calcific deposits not infrequently found in the "hypernephroid" carcinoma could conceivably gain access to the pelvis and ureter by invasion and set up spasm. This is perhaps of rare occurrence. In another case of stone in a pelvic carcinoma the pain was suprapubic. In the cortical series, 2 cases had pain in the right lower quadrant, simulating appendicitis. Generalized abdominal pain, distension, and tenderness were present in two instances, one of which was also accompanied by vomiting and resembled a true intestinal obstruction. Eisendrath and Rolnick42 suggest that many of these gastro-intestinal symptoms are reflex in origin and that the production of paralytic ileus is the probable cause of such occasional obstructive syndromes. Secondary or metastatic pain consisted of sciatic neuralgia in 3 cases, due to spinal involvement, pains in the ribs caused by secondary deposits and intractable headache in a case with parietal lobe metastasis. Spinal involvement may also give rise to neuralgia along the ilia-inguinal or iliohypogastric nerves, while at higher levels, a girdle distribution may be observed. 42 Secondary growths in any of the long bones may produce a deep seated type of bone pain; visceral discomfort often calls attention to metastases there, and other numerous possibilities exist because of the capricious mode of dissemination. MASS

The reported incidence of a mass, the third of the "classic" triad, again varies considerably and the figures range from 40 to about 80 per cent. 24 , 30 , 32 Mass 41 Howes, W. E.: Kidney tumors; classification, review of symptoms, methods of diagnosis, therapy, and end results. Radiology, 42: 319, 1944. 42 Eisendrath, D. N., and Rolnick, H. C.: In Urology, chap. 43, p. 774, 1938, J.B. Lipincott Co., Philadelphia.

678

NORMAN A. HARVEY

differs from pain and hematuria in that it is not so prevalent early in the clinical course, but often occurs relatively late. Perhaps its late occurrence is more apparent than real since the patient may often be unaware of its presence, while hematuria and pain are more impinging in character. For this reason the mass is often initially discovered by the examining surgeon. The mass is typically located in the flank and is firm, smooth, rounded, moves freely with respiration and is not particularly tender. Its mobility is impaired insofar as infiltration of the perirenal tissues has taken place. OTHER SYMPTOMS

Urinary symptoms (excluding hematuria) were seen initially or early in 40 per cent of the surgical series (table 5). The most common was dysuria, followed by frequency, urgency, pain and burning, in that order. The dysuria was usually associated with hematuria and the passage of clots, and in 3 such cases, frank retention developed. Frequency occurred almost as often as dysuria and was also commonly accompanied by hematuria perhaps for analogous reasons. Of the constitutional symptoms, weight loss was most frequent, then easy fatiguability, fever, and not uncommonly a combination of these occurred. In a few cases the initial symptom was unexplained weight loss, and twice, fever was the presenting feature. Creevy34 has called attention to the frequency with which fever is the principal early symptom. The total incidence of systemic reactions was surprisingly high, and equalled that of hematuria itself. As might be expected, they were more prevalent in the necropsy series (table 5). Symptoms referable to the gastro-intestinal tract took the form of anorexia most frequently and nausea and vomiting often occurred in conjunction. Constipation was not infrequent and flatulence and distension occasionally were seen. The suggestion that many of these gastro-intestinal upsets are reflex in origin has been alluded to above. The metastatic symptoms, excluding pain, consisted of sensory and motor disturbances in the legs due to secondary spinal carcinoma in 3 cases, metastatic masses on the ribs in 2 cases, cough due to growths in the lungs in 2 cases, and 1 case of tumor thrombosis in the inferior vena cava producing swelling of the ankles, penis, and scrotum. URINE EXAMINATIONS

Because gross hematuria is such a prominent symptom, it was of practical interest to compare the incidence of gross and microscopic blood in the urine in addition to noting any other elements. These urine reports were taken from previous clinical charts which were kept with no such project in mind, therefore this study is of the random variety and lacks the accuracy of a closely supervised one. Forty-four clinical records were studied with results as in table 7. The frequency with which many erythrocytes were noted microscopically in 44 cases was somewhat less (45 per cent) than the incidence of hematuria in the

679

KIDNEY TUMORS

whole series (59 per cent), but the total incidence of red cells in the urine (77 per cent) was greater than that of hematuria. White cells were a common finding, but they did not appear in large numbers as often as the red cells. Proteinuria was the most frequent urinary finding of all and was observed to some degree in all but 7 per cent of the cases studied. LeComte 40 has remarked the frequency of proteinuria in the absence of hematuria, and believes th~t it is due to congestion without infiltration of the pelvis. DIAGNOSIS

A . History and physical examination. The importance of an adequate history is obvious. However, the value of the physical examination is often vitiated by the lack of definite physical signs, but the examination should nevertheless be scrupulously performed on the chance that some lead may present itself. Early diagnostic signs are conspicuous by their absence. The value of the presence of left sided varicocele due to blocking of the left spermatic vein by tumor thrombus in the renal vein has been disparaged because of its rarity. 42 Its recent development should be suggestive, however. Begg43 describes an early diagnostic sign which he has observed in cases of upper pole TABLE

7.- Urinary findings in 44 cortical and pelvic tumors*t JUICS .

Many to loaded . .. ... . ...... .. . 0 to 25 per HPF ... ..... .... ... . None at any time .. .... .. . .. . ..

WBCS.

%

%

45 32 23

25 44 31

PROTEIN

%

2-4 plus

LPT-1 plus none

30 63 7

* Uncentrifuged specimens.

t Grossly bloody urines not included.

renal tumor, consisting of dilatation of the subcostal vein brought out by walking or standing. Bimanual palpation, although valuable, is often misleading, because 1) the kidney may be normally palpable, 2) the primary tumor may be too small to be felt and, 3) other swellings of the kidney or adjacent structures are difficult to differentiate by palpation alone. 34 General inspection in moderately advanced cases may indicate a slight anemia or evidence of recent weight loss. Metastatic nodules on the skin or bony surfaces may appear early or late in the clinical course . B . Roentgenography. The early use of x-ray offers the best opportunity for early detection of these tumors with derivative lifesaving consequences for the patient. X-ray investigations varying in completeness were carried out in 34 cases of the surgical series. The use of perirenal insuffiation in conjunction with x-ray is regarded as of limited value and should be employed with caution because cases of collapse following its use have been reported.44 43 Begg, R . C . : K idney growths in upper pole: early diagnostic sign. South African M . J. , 12: 131, 1938. 44 H yman, A. and Wilhelm, S. F .: Differential diagnosis of renal and suprarenal tumors . J . Urol. , 40 : 737 , 1938.

680

NORMAN A. HARVEY

Preliminary films of the abdomen may delineate masses more clearly and point the way for subsequent investigations. Sixteen such films were taken in our series. Eight of these were negative, while the remaining 8 demonstrated enlarged kidney shadows, 2 of these also showing renal calculus and 1 the presence 9f spinal metastases. The intravenous pyelogram has a definite place in the diagnostic armamentarium. It may obviate the use of cystoscopy and retrograde pyelography, a desirable feature for any patient, especially one with obscure abdominal symptoms, where the surgeon hesitates to perform the more strenuous procedure. It is of value in demonstrating bilateral polycystic kidneys when any doubt exists. Twenty excretion pyelograms were taken in this series. In 5 instances these sufficed to make the diagnosis, because of major changes in the pelvic pattern. Fifteen were made prior to the retrograde films. Five of these were TABLE

8.-Results of twenty-eight retrograde urograms EXTRA-PELVIC CHANGES

PELVIC CHANGES

Filling defect of pelvis plus blunting or obliteration of calices ... ... .......... Failure to inject pelvis due to ureteropelvic block....... . .. . . . . ........ ... a. Faint filling............ .. ..... . Dilated pelvis and calices (hydronephrosis) ..... . . ...... .... .. ...... . .. . Dilated pelvis alone ....... .. ......... . Elongated narrow pelvis .... ... .. ...... Elongation of one or more calices alone . Elongation of pelvis and one or more calices.... ......... ..... .. ......... . Elongation of major calices, obliteration of minor. . . . . . . . . . . . . . . . . . . . . . . . Displaced calices. . . . . . . . . . . . . . . . . . . . . . Stones. .. .. . .... ......... ..... . . .... ..

Enlarged kidney. . . . . . . . . . . . . . . . . . . . . . . . Displaced kidney . . . . . . . . . . . . . . . . . . . . . . . . a. Downward.. .. .... .. . .. ............ b. Upward (one rotated upward and 5* laterally also). . . . . . . . . . . . . . . . . . . . 1 Displaced ureter in lower pole tumor 4 (2 medially, 1 laterally). ... . . . . . . . . . . . 2 Dilated ureter . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2

10

10 5

3 2 3

2

2 1 1 4

* All pelvic tumors. inconclusive because of poor dye concentration* but the remammg 10 were of definite value, notably in 4 cases where the contrast medium could not be injected into the pelvis due to a block at the ureteropelvic junction and there the intravenous method depicted enlarged, hydronephrotic, poorly functioning kidneys. In 2 cases (both pelvic carcinomas) the excretion films were quite as satisfactory as the retrograde variety. The retrograde pyelogram is superior to the intravenous method for portraying finer detail and is a more generally reliable diagnostic procedure. It was used in 28 cases here, the results of which are tabulated (table 8) . The

* Beer 45 reported that tumor thrombosis of the renal vein is usually associated with poor dye excretion. Only 1 of our 5 cases came to autopsy, and renal vein tumor was present. 45 Beer, E .: Some aspects of malignant tumors of kidney. (B. A . Thomas oration) Surg., Gynec. & Obst ., 65: 433, 1937.

KIDNEY TUMORS

681

most common intrapelvic abnormality was a filling defect due to pressure on, or invasion of the pelvis, as shown by complete or partial amputation of one or more major or minor calyces. Mintz46 found this the most frequent pelvic deformity in 82 cortical tumors. Tapering of the calyces also occurred and was often associated with abbreviation. Tapering with elongation occurred in one instance, producing a typical "spider-leg" deformity. All 5 cases of complete obstruction of the ureteropelvic junction were seen in pelvic tumors and in 3 such instances stones were also present. A picture of hydronephrosis was seen 4 times, 1 in a pelvic tumor. Elongated pelvis occurred alone twice, and twice there was also elongation of one or more calyces. Mintz46 reports that elongation of calyces alone was the second most common finding in his series and usually just 1 calyx was involved, several being more indicative of polycystic kidney. The most common extrapelvic urographic change, besides enlarged kidney, was displacement of the renal pelvis and kidney as a whole, the direction being roughly away from the tumor site. Displacement or bowing of the proximal end of the ureter occurred in 3 cases, 2 in a medial, 1 in a lateral direction, with tortuosity in 1 case as well. Displacement of the pelvis and kidney were accompanied by pelvic deformity in only 2 of the 5 cases, contrary to the usual experience. 44 • 46 A diagnosis of kidney tumor was definitely made in 20 out of the 34 cases or 59 per cent, and was suggested in 15 per cent more. The comparative diagnostic efficiency of the retrograde and intravenous study in our small series was as follows: Retrograde pyelogram, 15 correct out of 28 performed or 54 per cent; intravenous, 7 correct out of 20, or 31 per cent. The comparative ease and simplicity of the intravenous urogram, plus the respectable number of successes would appear to argue for its widespread use as a preliminary to the more difficult retrograde method. Other diagnoses than the correct one were: non-functioning kidney in 4 cases, 2 of which showed calculus and secondary pyelectasis, hydronephrosis in 3 cases, inconclusive findings in 2 cases, question of extrinsic or intrinsic pressure displacing the kidney in 2 cases, and 1 diagnosis each of extrinsic tumor displacing the kidney and polycystic kidney. Roentgenologic investigation of the lungs and osseous system were routinely performed when a definite diagnosis of renal tumor was made (either preoperatively or postoperatively), and metastases were disclosed in 3 cases or 7.3 per cent. This compares with 56 per cent metastases by x-ray in the autopsy cases in which such antemortem studies were done.* Stones: There were 5 cases of renal calculus in 54 pelvic and cortical tumors. Four were in pelvic carcinomas, an incidence of 31 per cent, and 1 was in a cortical tumor, an incidence of 2 per cent. Differential diagnosis: The differentiation of renal tumor from other nearby

* Does not include 4•

the eight incidental cortical tumors. Mintz, E. R.: Roentgen diagnosis in 94 cases of renal tumor. J. Urol., 39: 244, 1938.

682

NORMAN A. HARVEY

pathological changes may be difficult and its remote metastases are notoriously confusing. The kidney mass itself is to be distinguished from such extrinsic tumors as enlarged spleen on the left, enlarged liver on the right, suprarenal tumor, retroperitoneal sarcoma, ovarian cyst, an other tumors of neighboring structures. This may be difficult even under the hands of an experienced clinician. In the case of extrinsic tumor displacing the kidney, x-ray usually fails to show any renal pelvic deformity, whereas renal tumor is said to do so almost invariably.44 · 46 However, in this series, 3 out of 5 such renal displacements due to intrinsic tumor failed to show any pelvic abnormality, and erroneous diagnoses were consequently made. Polycystic kidney may be detected by the distinctive excretion urogram, in addition to the history, bilaterality, concurrent hypertension, and other clinical features. Hydronephrosis with or without calculus may simulate or mask renal tumor both on physical examination and by x-ray, and in these cases the presence of some of the cardinal symptoms of kidney tumor may help distinguish the two conditions. Creevy34 makes the plea for clinicians to bear renal tumor in mind in their obscure cases and to rule it in or out by early use of the intravenous urogram. Only by such constant vigilance, he feels, will the percentage of early, surgically amenable cases be substantially raised. METASTASES

There were 100 per cent metastases in the autopsy group, excluding the incidental tumors. The necropsy findings in the eleven cases are shown along with data from three other autopsy series (table 9, fig. 2). Although these figures show some discrepancy in the relative frequency with which the various organs are implicated, it appears that the lungs are most frequently involved of the viscera, and that the visceral metastases outnumber the osseous variety. Creevy34 reports a higher incidence of bony metastases than most workers, and believes that a more thorough routine search for them in these cases would reveal a greater incidence. The true incidence of tumor thrombosis of the renal vein also varies more or less directly vvith the diligence-for which it is searched. McDonald and Priestley47 found 54 per cent renal vein tumor in a careful dissection of 509 hypernephromata, and conclude that the neoplastic cells enter the venules at the tumor site and grow by contiguity into the larger veins toward the hilus. Therefore, involvement of the renal vein and inferior vena cava is actually an invasion rather than metastasis since the tumor thrombi are extensions of the parent malignancy. The frequency with which such extension takes place offers a specious explanation for the numerous secondary growths in the suprarenals, liver, and opposite kidney, for many of these visceral deposits may result from extension into their respective veins from the 47 McDonald, J. R . and Priestley, J . T. : Malignant tumors of kidney; surgical and prognostic significance of tumor thrombosis of renal vein. Surg., Gynec ., & Obst., 77:

295, 1943.

683

KIDNEY TUMORS

inferior vena cava. Lehmann 48 pointed out that spread can take place in veins and lymphatics either in an antegrade or retrograde direction. In one of our cases a tumor thrombus in the inferior vena cava grew into the right atrium of the heart and also up into the hepatic vein for a distance of several centimeters. TABLE

9.-Ten most common locations of metastases in adenocarcinoma of the kidney AUTHOR, 11 CASES

Lungs . .. ..... . ... .... . .. Bones .. ... . . . .. . . ... . . .. Liver ... .. . .. ... .. .. . .. . . Lymph nodes ... ... . .. . . . Renal vein .... ...... . .. . Suprarenal gland . .. . . .... Opposite kidney ........ . Pleura .. . . .. . .. . ......... Brain and spinal cord .. . Pancreas .. . ....... . . . ...

qOfa f---+--

5---45% 4- 36% 3- 27% 5-45% 3- 27% 3- 27% 2- 18% 1- 9% 2- 18% 1- 9%

KO ZOLL ET AL., 44 CASES

JUDD&HAND,

29-66% 11- 22% 16- 36% 13- 30% 18- 41% 20-45% 13- 30% 8-9% 5---11% 4-9%

39-56% 11- 16% 13- 18%

70

CASES

5-

-+-- f - - - + - - - + - - 1 - - ---!--

7%

CJlEEVY, 92 CASES

COMBINED SERIES

40-43% 51- 55% 19- 21% 16- 17% 11- 12% 7- 8% 12- 13% 5--- 5% 6- 7% 5--- 5%

113- 52% 87-40% 51- 23% 34-23% 32- 22% 30- 20% 27- 18% 14-10% 18-8% 10- 7%

--1-- 1 - - ---1

BO

10 fuO

50 40

BO

~o 10 FIG. 2

The mechanism of tumor embolism probably explains the majority of lung metastases. Regional lymph node involvement occurs far less frequently in cortical tumor than in pelvic growths, and, logically enough, McDonald and Priestley47 found a commensurate scarcity of malignant cells in the perineural lymphatics in renal adenocarcinoma while observing a relative frequency of such cells in cases of pelvic tumor. 4 8 Lehmann, W.: Hypernephrommetastasen des skeletsystems . Arch. f. klin. Chir. 170: 331, 1932. (Cited by Creevy. )

684

NORMAN A. HARVEY TREATMENT

A diagnosis of kidney tumor having been established in a good risk patient whose opposite kidney is sound, there are but 2 considerations which may justify delaying surgical intervention. These are the question of preoperative irradiation and the presence of metastases. 49 The routine use of preoperative irradiation is impugned as a time-consuming procedure during which metastases may occur. The only mitigating circumstance is the case of a large fixed tumor where its use might facilitate the surgical removal. 49 • so, 51 Dean50 insists that such treatment does not render an "inoperable" tumor "operable", since in the inoperable state, locally speaking, the tumor has already grown through the capsule and has invaded the perirenal tissues. Waters 39 warns against too much preoperative palpation as a possible means of further dissemination. The presence of metastases is considered by most workers a grave obstacle to ultimate surgical success, although not completely inconsistent with surgery as was formerly believed. In Albrecht's 52 case, the patient had a metastasis to the scapula 4 years after nephrectomy, and was still alive and well 9 years after its removal, and there are parallel instances.53 Others49 • 60 point to the radiosensitivity of lung metastases which may be made to disappear by irradiation, and Bugbee49 suggests the further possibility of a mistaken diagnosis especially in the case of pulmonary growths. One group 28 found that bone metastases responded as well to irradiation as the secondary lung tumors, but this is not the prevailing opinion. 50 Lehmann 48 found that 13 out of 56 cases of bone metastases in the literature were of the solitary variety, as shown by autopsy or prolonged survival after extirpation. Although Creevy34 believes that this number is disproportionately high, he believes that solitary secondary bony growths do occur more frequently in this tumor. A valid contraindication at operation is a large fixed tumor, with extensive local infiltration and lymph node involvement. In these cases the immediate , surgical mortality is extremely high not to mention the 100 per cent fatal ultimate issue. The surgeon, therefore, should have no qualms about backing out in such ·instances. The presence of tumor thrombi in the renal veins and inferior vena cava cannot be considered as a contraindication in the light of the findings at the Mayo Clinic where 29 per cent of the cases with renal vein tumor survived more than five years. McDonald and Priestley47 have described 49

Bugbee, H. G.: Surgery of genito-urinary malignant tumors. J. A. M.A., 112: 298,

1939. 60 Dean, A. L., Jr.: Radiation therapy of tumors of renal parenchyma in adults. J. Urol., 39: 303, 1938. 61 Walters, W. : Malignant tumors of kidney and pelvis of kidney; 5 year cures following nephrectomy with partial or complete ureterectomy. Surg., Gynec., & Obst., 66: 445 , 1933. 52 Albrecht, P.: Beitrage zur Klinik und pathologischen Anatomie der Malignen Hypernephrome. Arch. f . klin. Chir., 77: 1073, 1905. (Cited by Creevy.) 63 Tavernier, L. : Hypernephrome metastatique. Survie durable apres nephrectomie et resection de la metastase humerale. Lyon Chir., 37: 345, 1941-42.

KIDNEY TUMORS

685

the nicety with which these thrombi must be removed and caution that merely "milking" the thrombus toward the kidney is a dangerously fallible technique. The actual surgical removal of these renal tumors is described in operative texts. Speaking generally, however, the use of the transperitoneal approach is reserved for the larger tumors where it offers the best exposure of the pedicle. Care must be exercised to avoid tearing the surface vessels of the kidney while retracting the peritoneum, and lumbar drainage of the kidney bed should be employed. 49 • 54 The lumbar route in conjunction with resection of the twelfth and even the eleventh rib as well, is used almost exclusively in the Rhode Island Hospital service and is adequate for the removal of most tumors. 55 Saklad, Sellman, and Howrie 56 warn of the occasional inadvertant rupture of the pleura which may occur in a particularly difficult removal, the physiological consequences of which the anesthesiologist should be ready to remedy. The usual supportive measures taken during and after nephrectomy are even more important in these cases in which blood and serum loss is apt to be more severe than in the ordinary resection and postoperative shock is to be anticipated. This is especially true following the removal of a large fixed mass where an extensive raw, oozing and bleeding surface is left, and, of course, argues against the removal of such tumors. In the surgery of papillary carcinoma of the pelvis it is generally agreed that complete nephroureterectomy, to include the intravesical portion of the ureter with a small cuff of bladder as originally expounded by Walters, 51 is the only reasonably good insurance against a recurrence of these neoplasms. Melicow29 believes that since these tumors also recur in the bladder or urethra, there may be a neoplastogenic proclivity of the entire urothelium. For those cases that are considered inoperable, irradiation often affords substantial relief from pain and may prolong life. 28 • 51 Walters 51 reports that 17 per cent of 41 inoperable cases treated with roentgen ray and radium lived more than 5 years, and 1 lived for 15 years. Local irradiation postoperatively has received perhaps less attention than as a preface to surgery, but it deserves serious consideration in view of the fact that one group found that immediate postoperative irradiation gave better results in terms of 5 year survival (42 per cent) than did irradiation followed by surgery (31 per cent). 28 SURVIVAL AND PROGNOSIS

Only 15 surgical cases were followed up for any appreciable length of time, and unfortunately most of these survivors were lost sight of before 5 years had elapsed. Smith, G. G.: Surgery of renal tumors. J. Urol., 39: 308, 1938. Personal communication. Dr. H.K. Turner, Chief of Urologic Service at the Rhode Island Hospital. 56 Saklad, M., Sellman, P. and Howrie, W. C., Jr.: Anesthesia and the urologic patient. Urol and Cutan. Rev., 49: 138, 1945. 64 66

686

NORMAN A. HARVEY

In 30 surgical cases the average preoperative history went back 10.2 months with a range of 2 days to 3 years. There was no apparent correlation between the duration of symptoms and the postoperative survival period, the longest survival (7 years, 3 months) occurring in the patient whose symptoms also antedated operation by the longest time (3 years) . Walters 51 found an average duration of the history to be 17 to 21 months and stressed the need for earlier recognition of this condition. The lack of correlation between length of history and postoperative survival is due to the presence of other more significant variables, such as tumor size, age and grade of malignancy. In 14 cases we found some degree of correlation between tumor size and survival period, the 2 being roughly inversely proportional (table 10). These figures especially indicate the correlation beTABLE SIZE

10.- Size of tumor and postoperative survival in fourteen cases SU1lVIVAL PERIOD

CAUSE OF DEATH

em.

3 6 6 8 8 8 10 12 15 15 16 16 19 20

4 years 3 years, 7 mos. 1 year, 2 mos.* 3 years* 1 year, 6 mos. 3 mos. 7 wks. 2 wks. 1 year, 6 mos. 6 mos. 2 days 1. day 7 years, 9 mos. 1 day

Metastases Metastases A. & W. when last seen A. & W. when last seen Metastases Metastases Metastases Metastases & postop. complies. Metastases Metastases Postoperative shock Postoperative shock Metastases Postoperative shock

* Free from metastases by x-ray at this time. tween tumor size and surgical risk, since several cases of large, fixed tumor died in a day or two of postoperative shock. Length of survival has been found closely related to Broder's index of malignancy by others. 22 • 51 In Priestley's large series, the survival of grade 1 adenocarcinoma was 3 times that of the grade 4 variety over a 3 year period, and the difference was even more marked at the end of 10 years. The extremely long duration of some of these well differentiated tumors is well known. Kraft 57 reported a patient with symptoms dating back 35 years, and Ljunggren's68 case had a palpable tumor for 30 years or more. Using the "clear cell" classification, Melicow29 found the prognosis progressively worse passing from the 57 Kraft, S.: Selbstheilung dei hypernephromen. Ztschf. f. urol. Chir., 16: 26, 1920. (Cited by Kozoll and Kirshbaum.) 68 Ljunggren, E.: Studien iiber klinik and prognose der Grawitzschen Nierentumor en zugleich ein beitrag zur frage nach der genese der hii.mat urie. Acta Chir. Scandinav ., (supp. 16), 66: 1, 1930. (Cited by Creevy .) ·

KIDNEY TUMORS

687

clear celled encapsulated variety to the granular celled type of adenocarcinoma. This observer also noted that a reversal of the appearance of the "classic triad", i.e., with mass presenting first, was usually associated with an unfavorable prognosis. Melicow and Cahill25 observed that the presence of calcification in hypernephroid tumors was an unfavorable omen, probably because of the fact that it occurs in lesions of longer standing. Tumor thrombosis of the renal veins was definitely linked with a decrease in the 5 year survival rate in McDonald and Priestley's series. 47 Survival statistics differ from place to place, but those of the large specialized clinics are uniformly the best. Priestley22 reports a 38.4 per cent 5 year survival for 502 cases of cortical tumor at the Mayo Clinic, while Bixler et al. 28 show a salvage of 42 per cent for a similar period at the University of Minnesota Hospital. This superiority of surgical results is partly due to a more discriminating selection of operative candidates, which greatly decreases the number of deaths directly attributable to operation. While some may believe that it is better to err on the side of radicalism in some of these apparently desperate cases, it has been our experience that this only results in a high operative mortality, and, far from saving the patient with a large fixed mass, his demise is only hastened. Furthermore, Walters51 showed a respectable 5 year survival rate (17 per cent) in inoperable cases treated with irradiation alone. The prognosis in carcinoma of the pelvis is not as favorable as in cortical tumor, and McDonald and Priestley47 found the outlook much poorer when there was lymphatic or venous involvement in the pelvic as compared with 1lhe cortical tumor. The prognosis for Wilms tumor is worse than that of either epithelial malignancy and the prognosis for sarcoma worst of all.22 PATHOLOGY

An apparent confusion of histological types of renal tumor exist and have given rise to an almost equally confusing number of classifications. The one employed here is based on Ewing's2 and excludes some of the rarer benign tumors. I. Epithelial tumors A. Cortical Tumors 1. Adenoma, single or multiple, arismg from renal tubules. .. 2. Adenocarcinoma, arising from renal tubules, and often from adenomas. 3. Adrenal tumors, or hypernephromas (rare). B. Pelvic Tumors 1. Papilloma 2. Papillary transitional cell carcinoma (common). 3. Epidermoid or squamous cell carcinoma (uncommon). II. Mixed Tumor (Wilms) III. Sarcoma The gross appearance of the various renal tumors offers little grounds for

J

688

NORMAN A. HARVEY

controversy but the microscopy of these tumors is a complex study which leaves divergent, contradictory impressions in the minds of different investigators. There were 8 incidental cortical tumors found at necropsy which were morphologically similar to the hypernephroid malignancies, i.e., they were of yelloworange color, fatty in consistency, and circumscribed. The question arose whether these growths should be considered essentially benign, and classed as "hypernephroid adenoma", after Kozoll and Kirshbaum, 17 or whether they were merely early stages of malignancy as Bell16 reasoned. Consequently, their histology was compared with that of 8 other tumors whose malignancy was unquestionable; these were all the primary cause of death and all had produced metastases. In addition 8 tumors removed surgically were submitted for further comparison (table 11). TABLE

11.-Histological features of eight incidental, eight surgical and eight inoperable renal cortical tumors

Clear cell predominating . . .... . .... . ........... .. . Clear and granular cell about equal. . . .. . ... . .... . Granular cell predominating . ... . . . . . . . . .. . ..... . . Cords . .. . . ... .. ..... . .. .. . ..... . ... ... . . . ... . .. . . Alveoli .. . .. . ...... . .. . . . .. .. . ... . .. ... . . . . .. .... . Tubules ........... . .......... . ... . . . .. . . . . ..... . . Papillary structure prominent .... . . . . . . ... . ... . . . Cystic blood-filled spaces ... ... .. ... . . . . . . .. .. . .. . Necrosis .. . .... . .... . ........ .... .... .. ... .. .. .. . . Calcification .... ....... ..... . . .. . ... . . .. ... . .. . .. . Lymphocytic infiltration . ... .. . . .. . .. . .. . ... .. ... . Pigmentation ..... . . .. ..... . ... . .. .. .. . ....... ... . Giant cell formation ..... . . .. .. ... . ... . ..... .. .. . . Capsule .. .. .......... . ......... . .. . .. .. ......... .

* Chosen at

INCIDENTAL

SURGICAL*

7 1

2 5 1 4 7 2 7 5 5 4 4 5 1 4

0

8 8 4 4

7 7 0 0 3

0

7

INOPERABLE

1

4 3 1 6

4 8

2 4 0 1

2 1 2

random from the 26 surgical adenocarcinomas .

The incidental tumors were largely of a predominating clear cell type, although a few granular cells occurred in half of the cases. The cell arrangements included solid cords, alveoli, and tubules, with many dilated thin walled blood vessels in the relatively scanty fibrous stroma. An obviously papillary structure was observed relatively infrequently. Necrosis was commonly seen, and there was pigmentation of some of the cells bordering on the cystic blood spaces. There were no evidences of advanced dedifferentiation such as tumor giant cell formation. On the contrary, there were the uniformity and regularity usually associated with a considerable degree of differentiation. There were distinct, integral capsules in 7 cases, the very small tumor not having grown sufficiently to form one. Of the symptomatic group of tumors, the necropsy specimens differed in the tendency toward a preponderance of the dark granular cell type, and in possessing a greater variety of cellular arrangements than the incidental tumors. The papillary and alveolar patterns were frequent and although the stroma

KIDNEY TUMORS

689

was vascular there were few dilated blood spaces. Capsule formation was not as frequent and when present was fragmentary and interrupted. No calcification was seen. There was only one slide showing tumor giant cell formation but lesser degrees of dedifferentiation were often observed. One tumor contained several hyalinized glomeruli (see below). The surgical group also showed a greater variety of cell arrangement, but the clear cell was usually numerically equal to, or predominant over the dark granular type. The largest number of degenerative and inflammatory effects were noted in the surgical group, several tumors showing calcification and lymphocytic infiltration, and also many polymorphonuclear leucocytes in l case. The remaining 18 surgical tumors that were also reviewed showed no strikingly different histological features from the 8 presented here. Many of the tumors contained a majority of clear cells in one section and granular in another, while in the same section the two were frequently juxtaposed. The clear cell was arranged in cords and alveoli, occasionally tubules also, on a background varying from a fine capillary stroma between the cords, to a coarser, connective tissue framework between groups of alveoli and tubules, suggesting in places a papillary structure. The clear cell tumors contained large dilated blood vessels. The regions where the dark granular cell predominated were apt to be lobulated in appearance because of the presence of interlacing bands of connective tissue, and had a pronounced papillary structure. The stroma was vascular but without the prominent dilation of the blood vessels. Microscopic foci of calcification were not uncommon and occasionally they were grossly visible. In l tumor there were numerous needle-like clefts similar in shape to cholesterol crystals. Dedifferentiation was seen in the sections of 3 surgical tumors, as tumor giant cell formation and swirling areas of spindle shaped cells, similar to sarcomatous tissue. Bracken59 believes that such sarcomatoid patterns are not examples of mixed malignancy but that the explanation lies in a reversion of the tumor cell back to the less differentiated form. In 5 tumors, there were hyalinized glomeruli seen in the connective tissue septa near the periphery of the tumor, and in 2 cases there were tubular structures lying in close apposition. These were interpreted as remnants of normal kidney structures which were bypassed by the expanding, infiltrating growth, not as "mixed" elements, although in several instances a rudimentary appearance was suggested. These observations differ in minor respects from those of the 2 previously mentioned investigators, and certainly might be subject to either interpretation. It is our belief, however, that the solitary adenoma which Weichselbaum and Greenish described as showing secondary change of fatty degeneration, cavernous blood vessels, and pigmentation, Ewing's "alveolar adenoma with large clear cells", the "benign hypernephroma" of Arkin, and the "hypernephroid adenoma" of Lubarsch, and Kozoll and Kirshbaum, are one and the same thing. Such a 59 Bracken, M. M.: Hypernephroma and spindle-cell sarcoma of kidney. 28: 13, 1936.

Am. J. Cancer,

690

NORMAN A. HARVEY

tumor would also explain the extremely long, benign courses which have been described. We believe that there is a benign form of "hypernephroid" tumor, which may and often does undergo malignant change. The pathology of the pelvic carcinomas was relatively simple. The papillary carcinoma occurred in 12 out of 13 cases, and there was 1 case of epidermoid carcinoma. In several of the papillary, transitional cell neoplasms, there were small foci of epidermoid metaplasia, especially in areas showing chronic inflammatory change. Histogenesis of the epidermoid carcinoma of the pelvis is supposedly on the basis of a leukoplakia due to chronic inflammation which is often associated with renal stone. 24• 25 There was a stone plus inflammatory reaction present in our case. DISCUSSION

The adrenal rest has been investigated in attempts to prove or disprove the Grawitz theory. Lubarsch found eight adrenal rests in 300 autopsies2, while in more recent years, Mitchell and Angrist60 uncovered 22 in 1,806 post-mortems. The latter60 noted 2 cases of adrenal rest associated with "hypernephromas" and felt that these situations were more than coincidental. However, the adrenal rest is found with greater frequency in other sites, such as the epididymis, broad ligament along the spermatic and ovarian veins, and on the under surface of the liver. 45 • 61 Ewing2 cites several reported cases of hypernephroma of the liver, broad ligament, retroperitoneal tissues, and ovary. Those reported in the ovary have been questioned, but several of the others appear to have been true adrenal tumors by their descriptions. Ai3 Ewing, Beer, and others reasoned, if the adrenal rest can give rise to a hypernephroma elsewhere, it is logical to assume that it may also do so within the confines of the renal capsule. The incidence of such renal tumors would be on the same order of frequency as the extrarenal hypernephroma, i.e., extremely rare, because there is no reason for assuming that environmental conditions in the kidney are any more propitious for malignant transformation of the adrenal rest than those elsewhere. Physiologically, the Grawitz theory is inadequate. There has been no generally accepted proof of any adrenal function in these tumors. 8•45 On the other hand, there is morphological evidence of a renal tubular function. Stoerk6 first compared the high lipoid content of the "clear cell" with the fat accumulations occurring in the diseased renal tubules in nephrosis. Schiller 7 believes that the hypernephroid cells demonstrate a reabsorptive capacity similar to that of the renal tubules in both hematuria and nephrosis. This function is manifested, he maintains, by the presence of blood pigment and hyaline droplets in those cells bordering on the cystic spaces which contain blood and proteinic fluid. The implications of this theory on the malignant gradations of these hypernephroid tumors is apparent. Since greater differentiation is associated in .other tumors with greater retention of function, though this is often altered or 60 61

Mitchell, N. and Angrist, A. : Adrenal rests in kidney. Arch. Path., 35: 46, 1943. Weisel and Neusser: Erkrangum der Nebennieren, Wien, 1910. (Cited by Ewing.)

KIDNEY TUMORS

691

heightened* an analogous situation may exist in the hypernephroid tumor. That is to say, the predominantly clear cell type of tumor, the hypernephroid tumor (both adenoma and carcinoma) is a well differentiated tumor of the renal cortex whose individual cells appear to manifest retention of tubular function by absorbing lipoid material, blood pigment, and proteins. On the other hand, the change toward the dark, granular cell is associated with a loss of that absorptive function, and is indicative of dedifferentiation and greater malignancy. Schiller7 employs embryological reasoning to explain the remarkable duplication of adrenal cortical tissue which occurs so frequently in the hypernephroid type of carcinoma, as follows: The prospective potencies to form adrenal cortex are widespread along the urogenital fold. The metanephrogenic tissue shares this potency which is more or less extinguished when the bud of the ureter "organizes" the production of renal tissue. However, some cells may remain which retain adrenal potentialities. He believes, from his observations on early papillomatous cysts, that first a tumor of renal character develops, then secondarily the adrenal potentialities become manifest with a resulting loss of polarity and the arrangement of the cells into solid cords. _ In the histogenesis of these tumors, there are two probable mechanisms, according to Schiller: 1) the convoluted tubules develop into cysts, which then become papillomatous and give rise to adenocarcinoma, and 2) in a small number of cases the papillary tumor may form directly from tubular epithelium without there being any intermediary cyst formation, and in these the demarcation is indistinct. The first mechanism could be applied to the hypernephroid tumor, while the second could explain the more malignant granular celled papillary adenocarcinomas, which are found most often in the inoperable autopsy group (table 1). The absence of blood filled cystic spaces in this group would explain the infrequency of early hematuria in these cases. Moreover, if the two mechanisms are valid, one might also postulate that all hypernephroid carcinomas have developed from hypernephroid adenomas, although in some cases the benign stage may be short-lived. The question has been raised whether these well diffentiated tumors discovered fortuitously at necropsy are really malignant tumors which would have asserted their qualities sooner or later, or whether they are benign tumors. We believe that there is a benign form of the tumor, and that much of the confusion arises from the fact that in the hypernephroid tumor we have a well differentiated neoplasm, that can, by virtue of its vascularity and accessibility to the renal vein and inferior vena cava, produce early metastases when it undergoes malignant changet.

* The "colloid carcinoma" of the glandular, secreting epithelium of the gastrointestinal tract for example. t It is somewhat analagous to the "metastasizing adenoma" of the thyroid gland in this respect. 62 •16 &2 Personal communication. Dr. B. Earl Clarke, Pathologist-in-chief at the Rhode Island Hospital.

692

NORMAN A. HARVEY SUMMARY

In a series of 54 pelvic and cortical tumors, 81.5 per cent occurred in the fifth, sixth, and seventh decades of life, and 70 per cent were in males. Hematuria was the most common initial or early symptom in the operable cases, while metastatic symptoms were the most frequent early features of the inoperable necropsy series. Microscopic urine studies in 44 cases revealed red cells in 77 per cent whereas the incidence of gross hematuria in the whole series was 59 per cent. Proteinuria was the most frequent urinary finding and occurred in 93 per cent of the cases. The value of the intravenous pyelogram in obscure cases and as a preliminary procedure is again stressed. The common sites of metastases and the mechanisms involved are discussed: The discriminating use of irradiation is called for in some cases. The survival period depends on several variables, including tumor size, age, and grade of malignancy. The nature of the hypernephroid tumor is discussed, and the literature is briefly reviewed with special reference to the Grawitz theory and the relations between the renal adenoma and adenocarcinoma. In our opinion the Grawitz theory is untenable as an explanation of the histogenesis of the large majority of renal cortical malignancies. McCormack General Hospital, Pasadena S, Calif.