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Jun 7, 1993 - Acta Pathologica Japonica 1993; 43: 674-682. Original Article. Renal cell adenomas and carcinomas in hemodialysis patients: Relationship ...
Acta Pathologica Japonica 1993; 43:674-682

Original Article

Renal cell adenomas and carcinomas in hemodialysis patients: Relationship between hemodialysis period and development of lesions

Satoru Takahashi,' Tomoyuki Shirai,' Kumiko Ogawa,l Katsumi Imaida,' Chikao Yamazaki,' Akira lto,' Kazuo Masuko2 and Nobuyuki Itol 'First Department of Pathology, Nagoya City University Medical School, Nagoya and 2Masuko Memorial Institute of Medical Research, Nagoya, Japan

Step-sections of 96 whole kidneys from 50 chronic hemodialysis patients were subjected to a histopathological and quantitative investigation with regard to the development of renal neoplastic lesions. The range of hemodialysis duration was from 1 to 222 months. A total of 349 renal cell adenomas were found in 41 cases (82%). They were commonly multiple and present bilaterally. Renal cell carcinomas were evident in four cases (8%), with hemodialysis durations of 54, 57, 112 and 222 months. The incidence of adenomas increased in a hemodialysis duration-dependent manner, indicating a high risk of renal cell tumor development in chronic hemodialysis patients. Furthermore, acquired cystic disease of the kidney (ACDK) was also observed in 12 cases (24.0%), where the mean hemodialysis period was 143.4 ? 48.0 months. This value was significantly longer than that of non-ACDK cases (P < 0.001). There was, however, no clear relationship between the appearance of ACDK and renal cell tumors. The present results underline the necessity for attention to possible neoplasia of the kidney in patients on long-term hemodialysis. Key words: acquired cystic disease, hemodialysis, human, kidney, neoplastic lesion

One of the most remarkable developments of medical technology is that patients with chronic renal failure can be maintained alive almost indefinitely by means of hemodialysis. The number of patients on hemodialysis is rapidly increasing, their numbers now reaching more than 100000 in Japan. However in recent years, several complications

Correspondence: Satoru Takahashi, First Department of Pathology, Nagoya City University Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467, Japan. Received 7 June 1993. Accepted for publication 20 July 1993.

accompanying longer survival of patients in relation to longterm hemodialysis have come to light, such as upper gastrointestinal tract disorders,' p,-microglobulin amyloid~sis,~-~ cardiovascular disease^,^-^ bone disease,*,9cystic transformation of the kidney1°-13and development of neoplasm^.^^-^* Moreover, it has been reported that patients with end-stage renal disease who require chronic hemodialysis or renal transplantation show a significantly increased risk of developing renal neoplasm^.^^-*^ In the present paper, the presence of neoplastic lesions in end-stage kidneys is described from 50 cases who had developed chronic renal failure from various renal diseases and had been maintainedon hemodialysisfor varying periods.

MATERIALSAND METHODS

A total of 96 kidneys from chronic hemodialysis patients were subjected to histopathological investigation. Included were bilateral kidneys from 46 autopsy cases and three autopsy and one surgically resected single organ. The other kidney in the three autopsy cases had been resected due to renal cell carcinoma (case 38), polycystic disease (case 44) and for the purpose of renal transplantation (case 50), respectively. Other than these, none of the cases had any history of renal transplantation. The mean age was 65.0 years (44-84 years, 33 males and 17 females), and the mean duration of hemodialysis was 66.5 i 63.8 months (1-222 months). All specimens were fixed in 10% buffered formalin for 3-7 days and then were sliced into step-sections at 3-4 mm intervals. Following dehydration and paraffin embedding, 4-5 pm sections were stained with hematoxylin-eosin (HE) for histopathological examination. Periodic acid-Schiff (PAS) staining was also performed as the occasion demanded.

Neoplastic lesions in hemodialyzed kidneys

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Table 1 Histopathological findings in the 50 cases of hemodialyzed kidneys investigated Case no.

Agelsex

Duration of HD (months)

53 M 71 M 65 M 58 M 61 F 84 M 75 F 66 F 63 F 81 M 65 M 80 F 65 M 65 M 64 F 51 M 66 M 64 M 81 F 66 M 70 F 57 M 77 F 69 M 61 M 63 M 75 F 59 F 44 M 72 F 46 M 52 M 57 M 78 F 66 M 80 F 55 M 65 M 76 M 66 M 71 M 60 M 62 F 64 F 58 M 65 M 73 F 67 M 50 M 46 M

1 1 1 1 1 1 1 3 3 4 6 6 7 9 11 15 18 19 19 30 35 39 40 45 49 54 62 69 70 70 71 73 85 89 90 93 100 105 111 112 134 137 140 156 166 166 180 186 218 222

Renal cell tumor Ad Ca

ACDK

Cause of CRF

Other malignancy

~

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50t

-

+ + -

+ + + + + + + + + + + + + + + + + + + + +

+ + + + + + + + +

+ + + + + + + + +

DM DM DM DM CGN CGN CGN DM DM DM AMY GS PCK CPN CPN DM DM DM CGN DM DM DM DM CGN CGN DM CGN DM CGN CGN DM DM CGN GS GS CGN Unknown Unknown GS CGN CGN GS CGN PCK CGN CGN Unknown DM CGN CGN

Paget's disease HCC

Prostate (adc) Prostate (adc) Lung (SCC) Prostate (adc) Lung (adc) HCC

Bile duct (adc) Prostate (adc)

Prostate (adc) Prostate (adc)

*Tumor was resected at the 57th month of hemodialysis. No carcinoma was evident in the remaining kidney. +Renal transplantation was performed after a 100 month period on hemodialysis. Six months after transplantation, the graft was removed due to rejection, and hemodialysis was continued. DM, diabetic nephropathy; AMY, primary amyloidosis; GS, benign glornerulosclerosis; PCK, congenital polycystic kidney disease; CGN, chronic glomerulonephritis; CPN, chronic pyelonephritis; HCC, hepatocellular carcinoma; adc, adenocarcinoma; SCC, squamous cell carcinoma; Ad, adenoma; Ca, carcinoma; ACDK, acquired cystic disease of the kidney; HD, hemodialysis; CRF, chronic renal failure; NA, not available.

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S. Takahashi eta/.

Renal cell adenomas and carcinomas were diagnosed with reference to the criteria of Thoenes et a/.24 Adenomas comprised grade I tumors up to 2cm in diameter. Carcinomas included grade I tumors in excess of 2 cm in diameter as well as grade II and 111 tumors of any size. The size of tumors and total areas of kidney sections were measured using a color video image processor (VIP-21C, Olympus-lkegami Tsushin Co., Tokyo). The numbers and areas of the tumors were also expressed per unit area of the kidney. Statistical analyses were performed using the two-tailed Fisher’s exact test and the Student’s t-test. For comparison of hemodialysis duration with numbers and areas of renal cell adenomas, single linear regression analysis was applied.

tively intense red color in HE stained preparations (Fig. 5); and (iv) basophilic cell type: small cells with a relatively high nucleocytoplasmic ratio and cytoplasm tending to appear bluish in HE preparations (Fig. 6). The basophilic type was most common (43.4%; Table 3), but chromophobe lesions predominated in patients who had received < 60 months of hemodialysis. There was no specific histological type of adenoma associated with hemodialysistreatment. Renal cell carcinomas were evident in four cases, one being present in a kidney resected during hemodialysis (in the 57th month, case 38). Among the four cases, two were clear cell type (cases 26, 50) and the remaining two were granular cell type (cases 38, 40). None demonstrated any metastasis.All were found together with an adenoma in either the same or the other kidney.

RESULTS Table 1 summarizes individual histopathological diagnoses for the dialyzed kidneys in all 50 cases investigated. Renal cell adenomas were observed in 41 (82.0%)and carcinomas in three (6.0%).The total number of renal cell adenomas was 349. They were commonly multiple and present bilaterally, and the majority were < 1 cm in diameter. Quantitativeanalysis of renal cell adenomas revealed that their numbers and areas increased in proportion to the duration of hemodialysis (Table 2) with a correlation coefficient of r = 0.413 (P < 0.01) and r = 0.428 (P < 0.05), respectively (Figs 1,2). Average numbers and areas of renal cell adenomas in the 33 male patients investigated were 0.091 ? 0.123 (/cm2) and 0.281 +- 1.039 (mm2/cm2),respectively, and those in the 17 0.044 female cases were 0.049 2 0.074 (/cm2)and 0.025 (mm2/cm2).There were no differences in renal cell adenoma development between males and females. Renal cell adenomas were classified into the following four types: (i) clear cell type: characterized by abundant non-staining cytoplasm (Fig. 3); (ii) chromophobe cell type: lightly translucent cytoplasm filled with fine reticular filaments (Fig. 4); (iii) eosinophilic cell type: cytoplasm with compara-

*

Table 2 Quantitative results for renal cell adenomas in hemodialyzed kidneys

Duration of hernodialysis (months) 1-12 13-60 61-120 121-222

No. cases examined

Renal cell adenoma No. (/cm2) Area (rnmz/crn2)

0.6

0 N^ 0.5]

0 0.4 I

m

m

I

E 0.3 c 0

8

0.2

u

IT 0.1 0

=

o 1

!

0.012 2 0.021 0.051 2 0.046 0.139 f 0.153 0.115 ? 0.120

0.009 It 0.027 0.023 t 0.029 0.081 2 0.120 0.817 f 1.832

The values for renal cell adenoma represent the mean t s.d.

, 25

,

~ 50

. 75

,

, 100

,

, 125

,

,

150

, 175

,

, 200

.

, 225

,

, 250

Durationof hemodialysis (months)

Figure 1 The relationship between the duration of hemodialysis and the number of renal cell (RC) adenomas. Regression analysis revealedthe formula of no. = 0.001DH + 0.029, r = 0.413, P < 0.01. Each circle represents an individual adenoma.

-.

71

I

0

0 IT

-

1

Z o

a

I

I

0

15 11 14 10

.

0

.

I.

25

50

75

100

125

150

175

200

225

250

Durationof hernodialysis (months)

Figure 2 The relationship between the duration of hernodialysis and the area of renal cell (RC) adenomas. Regression analysis revealed the formula of Area = 0.006DH - 0.185, r = 0.428, P < 0.05. Each circle represents an individual adenorna.

,

~

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Figure 3 Clear cell type of renal cell adenorna in case 26.Note the tubular structure and the highly transparent, abundant cytoplasm. (a) Low power field, (b)higher magnification (HE).

Table 3 Histological cell types of renal cell adenornas in hernodialyzed kidneys Duration of hernodialysis (months)

Clear

Chrornoprobe

Chromophilic Total Eosinophilic Basophilic

2 (4.5) 5 (8.3) 8 (5.6) 5 (4.9)

28 (63.6) 9 (20.5) 24 (40.0) 18 (30.0) 33 (23.2) 35 (24.7) 33 (32.0) 19 (18.4)

~~

1-12 13-60 61-120 121-222 Total

5 (11.4) 13 (21.7) 66 (46.5) 46 (44.7)

44 60 142 103

20 (5.7) 118 (28.3) 81 (24.8) 130 (43.4) 349

All values in parenthesesrepresent percentages

Dunnill et a/. earlier reported that long-term hemodialysis led to multicystic changes in end-stage kidneys, coining the term acquired cystic disease of the kidney (ACDK).'O When multicystic lesions occupied more than 40% of the kidney

that had no prior history of congenital polycystic kidney disease, ACDK was diagnosed. The mean hemodialysis duration in the 12 cases of ACDK was 143.4 5 48.0 months. This value was significantly longer than that of the 36 nonACDK cases (Table 4). Renal cell adenomas and carcinomas were present in all (100%) and two (16.7%) of the ACDK cases, respectively. These values were not significantly different from those of non-ACDK cases. Quantitative data for the numbers of renal cell adenomas but not areas were significantly higher in ACDK cases than non-ACDK cases. Malignant tumors of organs other than the kidneys were found in 12 cases (24.0%); six prostatic adenocarcinomas, two hepatocellular carcinomas, two lung carcinomas (one squamous cell carcinoma and one adenocarcinoma), one bile duct adenocarcinoma and one Paget's disease. The most common primary renal disease responsible for chronic renal failure was diabetic nephropathy, which was present in 19 cases, followed by 18 cases of chronic glomerulonephritis, five cases of benign glomerulosclerosis, two

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Figure 4 Chromophobe cell type of renal cell adenoma in case 41. Note the tubular structure, light translucence and abundant cytoplasm. (a) Low power field, (b) higher magnification (HE).

Table 4

Comparison of ACDK and non-ACDK cases in hemodialysis patients* No. cases

ACDK Non-ACDK

12 36

Averane duration of HD (month) 143.4 ? 48.0t 40.0 2 43.5

Renal cell adenomas Incidence (“3)

No. (/mm2)

Area (mm2/cm2)

12 (100) 27(75)

0.141 f 0.114$ 0.057 f 0.106

0.753 ? 1.669 0.021 2 0.035

Incidence of renal cell carcinomas (%) 2 (16.7) 1 (2.8)

*Two cases of congenital polycystic kidney disease were excluded from the data. tSignificantly different from non-ACDK cases at P < 0.001.$Significantly different from non-ACDK cases at P < 0.05. HD, hemodialysis. The values for the average duration of H D and the number and area of renal cell adenomas are the mean t s.d.

of chronic pyelonephritis, two of congenital polycystic kidney disease and one of primary amyloidosis. The mean survival time after acceptance of hemodialysis in patients with diabetic nephropathy (36.8 i- 45.0 months) was significantly shorter (P < 0.01) than with chronic glomerulonephritis (91.9 i 70.4 months)

DISCUSSION The present study clearly demonstrated that the development of renal cell adenomas increased in a hemodialysis duration-dependent manner. This result is compatible with that renal neoplasms are more previous f i n ~ i i n g s , ’ ~ namely, -*~

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Figure 5 Eosinophilic cell type of renal cell adenoma in case 31.Tumor cells have cytoplasm with a comparatively intense red color. (a) Low

power field, (b)higher magnification (HE).

frequent in patients receiving chronic hemodialysis. The increase in both number and area of the tumors with time on hemodialysis suggests that both initiation and development growth are enhanced. The reasons for this acceleration of renal cell tumor development by hemodialysis are however, unclear. The major type of renal cell adenomasfound in the present study changed from chromophobe cell to basophilic cell types at the point of approximately 60 months duration of hemodialysis.The clear cell type of adenoma was comparatively rare at all stages, while the most common renal cell carcinomas are, in general, of this type. In view of the expected adenoma-carcinoma sequence, the discrepancy in these results suggests a differential ability of benign lesions to progress to malignancy. All the present malignant lesions were well differentiatedtypes although there have been a few cases of sarcomatoid renal cell carcinomas arising with ACDK reported in the l i t e r a t ~ r e . ~ ~ , ~ ~ Several researchers have asserted that malignancy in vari-

ous organs is more frequent in patients with chronic renal The predispositionto cancer development in such cases has been reported to be due to a weakened immune system, represented by a decreased number of lymphocytes, shortened lymphocyte survival, inhibition of lymphocyte transformation and suppression of T cell activities2' A higher concentration of N-dimethylnitrosamine, one of the carcinogenic nitrosamines, was also detected in the peripheral blood of long-term hemodialysis patients,28the reason considered partly to be due to intra- and/or extracorporeal p r o d u c t i ~ n Thus, .~~~~ this ~ finding suggests that nitrosocompounds may play a role in the development of renal tumors in hemodialysis patients. The overall occurrence rates for ACDK in dialysis patients have been reported to be 30-40% in autopsylnephrectomy The pathogenesis of ACDK is still not understood. It may be that the cysts represent dilated tubules or collecting ducts which have become obstructed as a result of surrounding interstitial fibrosis or by oxalate crystals which

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Figure 6 Basophilic cell type of renal cell adenoma in case 39. Tumor demonstrates papillary projections. Note small cells with slightly bluish cytoplasm. (a) Low power field, (b) higher magnification(HE).

are plentiful under these conditions. Additional detailed information of ACDK is therefore required. Since the average duration of hemodialysis in the 12 ACDK cases was significantly longer than that of non-ACDK cases, long-term hemodialysis may be a risk factor for ACDK development. While renal cell tumors were observed more frequently in ACDK cases, a consideration of the influence of the hemodialysis period common to both ACDK and tumors suggests that cystic changes are independently induced and may not necessarilyincrease the risk of renal cell tumor development. The association may thus simply be a reflection of duration. Sasagawa et a/. reported that the incidence of prostatic cancer in hemodialysis patients was six times higher than in the general p o p ~ l a t i o n In . ~the ~ present study, six prostatic adenocarcinomas (18.2%), all latent cancers, were found among the 33 males, whose mean age was 62.1 k 9.4. The value of 18.2% is not significantly different from the age-

adjusted overall prevalence (20.5%) of latent prostatic cancer in 576 Japanese men.% Therefore, the data in the present study do not provide any support for an association with hemodialysis. Further investigation is needed to clarify any relationship between clinical prostate cancer development and hemodialysis. It would clearly also be of interest to analyze whether the hemodialysis-associatedrenal cell carcinomas demonstrate the chromosome 3p deletion and loss of heterozygosity reported for sporadic, non-hereditary lesions,35especially in view of the difference described between papillary and nonpapillary It was found earlier that in hemodialysis patients, these two types each accounted for approximately 50%.37 The advent of long-term hemodialysis has led to marked prolongation of life in patients with uremia due to chronic renal failure. With 116 303 hemodialysis patients in Japan at

Neoplastic lesions in hernodialyzed kidneys the end of 1991,38 or 937.6hnillion population, and 22 960 of these individuals being on dialysis for more than 10 years, the risk 'IS considerable. Patients with end-stage renal disease who require chronic hernodialysis or renal transplantation show a significantly increased risk of developing renal cell carcinomas more than 7-50 times the incidence in the general l p o p u l a t i ~ n . ~ ~ ~ ~ ~ ~ ~ ~ Particular attention therefore needs to be paid to the development of renal cell tumors in patients who receive hemodialysisfor more than 5 years. The findings presented here reinforcethe need for routine screening of whole organs in such cases.

13 Gehrig JJ, Gottheiner TI, Swenson RS. Acquired cystic disease of the end-stage kidney. Am. J. Med. 1985;79: 609-620. 14 Matas AJ, Simmons RL, KjellstrandCM, Buselmeier TJ, Najarian

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ACKNOWLEDGEMENTS The authors wish to thank Mieko Kawai for her excellent preparation of histopathologicalslides. The work was supported in part by grants from the Society for the Promotion of Pathology in Nagoya, Japan.

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