Metastatic Renal Cell Carcinoma Associated With Acquired Cystic Kidney Disease 15 Years After Successful Renal Transplantation Yeong-Hau H. Lien, MD, PhD, Igal Kam, MD, Paul F. Shanley, MD, and Gerhard P. J. SchrOter, MD • Renal cell carcinoma (RCC) is a relativelyuncommon cancer in renal transplant patients. From 1968 to 1987,101 cases of RCC of native kidneys have been reported to the Cincinnati Transplant Tumor Registry. We describe here a case of metastatic RCC associated with acquired cystic kidney disease (ACKD) 15 years after successful renal transplantation. The patient presented with a subcutaneous nodule, which led to discovery of a large primary tumor in the left kidney. ACKD was present in the atrophic right kidney. The reported cases of ACKD-associated RCC in renal transplant recipients were reviewed. Most of these cases are middle-aged men with a long posttransplant course, good graft function, and usage of azathioprine and prednisone as immunosuppressive agents. ACKD can develop or persist and progress to RCC many years after successful renal transplantation. Transplant patients with flank pain, hematuria, or other suspicious symptoms should have imaging studies of their native kidneys. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Acquired cystic kidney disease; renal cell carcinoma; renal transplantation.
~ N INCREASED prevalence of renal tumors ftin patients with acquired cystic kidney disease (ACKD) associated with chronic dialysis has long been recognized. l -4 A recent populationbased study by Port et al shows a fivefold increase of invasive renal cell carcinoma (RCC) in this setting as compared with the general population. 5 Ishikawa et al6 observed regression of ACKD after successful renal transplantation. Vaziri et aC suggested that the presence of a functioning renal graft may retard the evolution of cystic changes in the native kidneys. However, we describe here a case of metastatic RCC associated with ACKD discovered 15 years after successful renal transplantation. This case represents the longest interval between transplantation and diagnosis of ACKD-associated RCC in the literature and indicates that the malignant potential of ACKD remains even after many years of normal renal function. CASE REPORT A 44-year-old white man with end-stage renal disease due to chronic glomerulonephritis received a cadaveric renal allograft in April 1974, 5 weeks after initiation of hemodialysis. The allograft was rejected within I month. He was treated with pulse steroid therapy (methylprednisolone I g every day for four doses) and local irradiation (150 rad every other day for three doses) without success. The rejected kidney was removed and replaced by another cadaveric renal graft in June 1974. He received a 2-week course of antilymphocyte globulin postoperatively, and did not have any episodes of acute rejection after the second transplantation. In May 1989, 15 years after the second renal transplantation, he presented with a nodule on the right shoulder, which had increased in size over several months. He had normal renal function and was taking
prednisone 10 mg/d, azathioprine 50 mg/d, furosemide 40 mg/d, captopril 50 mg/d for hypertension, and allopurinol 200 mg/d to prevent recurrent gout. He denied weight loss. The patient appeared healthy and had a blood pressure 130/90 mm Hg, and a pulse rate of 76 bpm. A mass with violaceous discoloration of the skin, approximately 4 cm in diameter, was palpable on the right shoulder anteriorly. Otherwise, physical examination was unremarkable. He had no lymphadenopathy or hepatosplenomegaly. Laboratory studies included hematocrit, 51.8% (hematocrit had been fluctuated between 44.1 % and 54.3% since 1975); white blood cell count, 7,800/mm 3, with neutrophil 84%, lymphocyte 10%, and monocyte 6%; serum sodium, 138 mmol/L (mEq/L); potassium, 3.7 mmol/L; CI, 107 mmol/L; CO 2 , 23 mmol/L; blood urea nitrogen (BUN), 6. 1 mmolfL urea (17 mgjdL); creatinine, 97 I'mol/L (1.1 mgjdL); Ca, 2.4 mmol/L (9.6 mg/dL); phosphate, 0.94 mmoljL (2.9 mgjdL); albumin, 40 gIL (4.0 gjdL); aspartate aminotransferase (AST), 94 IU/L; alkaline phosphatase, 200 IU/L. Urinalysis showed no proteinuria or hematuria. Chest x-ray showed clear lung fields without lymphadenopathy. An excision biopsy of the right shoulder nodule was performed and showed clear cell carcinoma (Fig lA). This finding prompted a computed tomography (CT) scan of the abdomen with contrast medium (Fig 2), which showed a 7 X 7 Xcm 5 lobular mass with low-density areas in the left kidney. The right kidney was atrophic and measured 3 X 3 X cm 4 with several 3- to 5-mm cysts and calcification. No evidence of From the Departments of Medicine, Pathology, Surgery, and Pediatrics, University ofColorado H ealth Sciences Center, Denver, CO. Y-H.H.L. is supported by a National Kidney FoundationBurroughs Wellcome Fellowship Award. Address reprint requests to Yeong-Hau H. Lien, MD, PhD, Department of Internal Medicine, Section of Renal Disease, University ofArizona, Tucson, AZ 85724. © 1991 by the National Kidney Foundation, 1nc. 0272-6386/ 9 J/ J806-00 J5$3.00/ 0
American Journal of Kidney Diseases, Vol XVIII, No 6 (December), 1991: pp 711-715
711
712
LIEN ET AL
Fig 1. Histopathology of (A) right shoulder mass, and (B, C, D) the left kidney (H&E; original magnifications: A, X 85; B, X 85; C, X 175; D, X 35). (A) Metastatic RCC in skin. Subcutaneous connective tissue is shown in the upper left corner. (B) RCC in the upper left corner and atrophic renal tissue with microcystic changes on the right side. (C) RCC, clear cell type in high-power view. (D) Invasion of RCC to renal vein.
filling defect in the left renal vein or the inferior vena cava was found. The renal allograft and the liver were normal. He underwent a left nephrectomy on May 25, 1989. The removed kidney measured 8 X 6 X 5 cm and had a markedly nodular surface. The tumor was multinodular and yelloworange, with focal areas of interlacing gray apparent connective tissue. The tumor obliterated renal architecture, invaded to the left renal vein, and extended through the renal capsule into perirenal fat. Microscopic examinations showed many microcysts in the atrophic renal tissue adjacent to the tumor (Fig IB). The cysts were lined by flat to cuboidal epithelium. Tumor cells were large and round to polygonal, with clear cytoplasm and moderately pleomorphic nuclei, consistent with clear cell carcinoma (Fig I C). Tumor invasion of renal vein was demonstrated microscopically (Fig ID). The patient did not receive chemotherapy and remained on immunosuppression. Subsequently, serial CT and a magnetic resonance imaging (MRI) scans performed 3 to 6 months after nephrectomy showed mUltiple pulmonary nodules, a small hepatic lesion, several subcutaneous lesions, and a lytic bone lesion in the right iliac bone.
DISCUSSION
We describe here a case of metastatic RCC associated with ACKD in the presence of a functioning renal graft for 15 years. The primary tumor and ACKD were discovered only after excision of a subcutaneous metastasis. The association of ACKD with chronic hemodialysis was first recognized by Dunnill et al. l ACKD occurs in 30% to 90% of dialysis patients and the prevalence increases with the duration of dialysis. The association of renal tumor with ACKD has also been recognized. I •4 Based on a review of the literature, Gardner and Evan3 calculated a prevalence of 25% for renal tumor and of 4.5% of RCC per se in dialysis patients with ACKD. More recently, Port et al 5 have reported a fivefold increase of invasive RCC in dialysis
713
POSTTRANSPLANT RENAL CELL CARCINOMA
Fig 2.
with age ranging from 39 to 58 years. Men also predominate in dialysis patients with ACKD associated RCC with a male to female ratio of 3.8: 1.4 Male gender may be a predisposing factor for the development ofRCC in patients with ACKD. The primary renal disease was chronic glomerulonephritis in five and malignant hypertension in one case. The duration of dialysis before transplantation was in the range of2 months to 5 years and duration of transplant was 2 to 15 years. Our patient had the shortest duration of dialysis and the longest duration of renal transplant. Interestingly, five of six patients had renal transplant for more than 5 years at the time of diagnosis of RCC. All of the patients had good graft function. The immunosuppression therapy was known to be azathioprine and prednisone in six cases. Two ofthese patients presented with flank pain. One presented with back pain and fever. One presented with a pulmonary nodule 3 years after removal of a "renal cell adenoma" incidentally during bilateral nephrectomy for recurrent urinary tract infection. Our patient presented with a subcutaneous nodule. The last patient was asymptomatic and RCC was diagnosed because he was followed regularly by CT scan of the native kidneys after transplantation. 12 Judging from the available data, all of these reported cases had malignant RCC because the tumors were large or multifocal, or had metastases. Four cases had documented metastases of RCC and one had a rupture of the tumor. Interestingly, the case re-
Abdominal CT scan with contrast shows a 7
x 7 x 5 cm lobular mass with low-density areas in the
left kidney. The right kidney is atrophic and measured 3 x 3 x 4 cm, with several 3- to 5-mm cysts and calcification.
patients compared with the general population in metropolitan Detroit. In Japan, a recent 10year prospective study by Ishikawa et al 8 has shown that ACKD progresses in dialysis patients and the incidence of RCC in these patients is 57 to 134 times higher than in general population. It is clear that the risk of RCC increases significantly in dialysis patients with ACKD. The association ofRCC and ACKD in renal transplant recipients has not been well addressed. Table I lists the reported cases of well-documented ACKD and renal tumors in renal transplant recipients, including the present case. 7 ,9.I3 Among them, six cases have adequate clinical information for analysis. All six of these cases are men,
Table 1. Reported Cases of ACKD Associated Renal Tumors in Renal Transplant Recipients Primary Aenal Author
Vaziri'
Age/Sex
Disease
Duration of Dialysis/AT
Graft Function
NA 46/M
NA CGN
NA 5 yr'/5yr
NA Good
45/M
HTN
3 yr/2 yr
Good
49/M
CGN
10 mo/ll
Ishikawa'2
39/M
CGN
Almirall'3
58/M
Present case
44/M
Arias' Faber10
Ludmerer
11
..
Immunosuppresskln AZA/PAED NA AZA/PRED
Presentation NA Flank pain, hematuria Flank pain
Mu~ifocal RCC 7 ·cm RCC with rupture
0.5· to Ik:m ACC, bilateral, Met: lymph nodes/lungs 2 ACC, one 2.4 cm, no met 7·cm ReC, Met: bones/lungs Ik:m RCe, renal vein invasion, Met: skin/ bones~iver/Iungs
RCC, Met: lymph nodes~ungs/bones
So. ~
1.6
AZA/PRED
Pulmonary nodules
8 mo/8 yr
So. ~
1.3·1.6
AZA/PRED
Asymptomatic
CGN
5 yr/7yr
Sc. ~
1.1
AZA/PRED
Back pain, fever
CGN
2 mo/15 yr
So. ~
1.1
AZA/PRED
Subcutaneous nodule
yr
Pathological Findings
, Duration of dialysis prior to transplantation. Abbreviations: RT, renal transplant; CGN, chronic glomerulonephritis; HTN, hypertension; AZA, azathioprine; PRED, prednisone; RCe, renal cell carcinoma; S"" serum creatinine (in mg/dL); Met, metastases; NA, not available.
714
ported by Ishikawa et al l2 had a slow growing RCC, which was retrospectively found by CT scan (1.2 cm in size) taken 7 years before the diagnosis of RCC. A series of CT scans showed that the growth of the tumor was parallel to the progression of ACKD. The clinical course of this case was similar to the ACKD-associated renal adenomas in dialysis patients. Penn 14 reported a case of "epithelioma" in a transplant patient under cyclosporine therapy. The tumor was incidentally discovered in the wall of a renal cyst. 14 This case is not included in Table 1, because ACKD was not documented. In the two largest series of transplant recipients with ACKD, one case of RCC was found in each, but no benign renal tumors were reported histologically in 11 cases? and radiographically in 26 cases. IS Whether the presence of ACKD increases the risk of developing RCC in renal transplant recipients is unclear. Earlier, in a Scandinavian series,16 four of 112 malignancies encountered in 3,956 renal transplant recipients from 1969 to 1978 were RCC, with three involving native kidneys and one involving the allograft. The prevalence ofRCC of native kidneys in this study was 0.08%. More recently, Penn and Brunson 17 reported that the frequency of RCC as de novo malignancies following cyclosporine therapy was 23 of 412 tumors, with 22 involving native kidneys and one involving allograft. The investigators suggested that the high frequency of RCC may be related to ACKD; however, whether ACKD was present was not mentioned in this study. Dlugosz et al lS reported that metastatic RCC of native kidneys accounted for 2% of deaths in 222 renal transplant recipients over an 18-year period. They also suggested that the incidence of RCC may be higher in these patients. Since most reports of ACKD-associated RCC do not indicate a population at risk, it is difficult to estimate the incidence ofRCC in renal transplant recipients with ACKD. In a prospective study by Ishikawa et al, one of 26 renal transplant recipients with ACKD developed RCC. IS However, it could be a chance occurrence. The low reported rate of ACKD-associated RCC may be due to the lack of recognition of the association ofRCC with ACKD in transplant patients, long induction time of RCC from renal cysts, and difficulty in diagnosis of RCC in native atrophic kidneys.
LIEN ET AL
Yoshimura et al l9 reported a case of metastatic RCC of the spine and liver 4 years after transplantation. A small primary RCC in a native kidney was only identified at autopsy. We believe that once the association between ACKD and RCC is recognized, more cases of ACKD-associated RCC in transplant patients will be discovered in the future. Our patient had ACKD despite good renal graft function 15 years after transplantation. The effect of restoration of renal function by renal transplantation on ACKD has been addressed. Ishikawa et al6 reported resolution of acquired cysts with shrinking of native kidneys in two of three patients 8 to 10 months after successful renal transplantation. The third patient had incomplete involution of the cysts. Vaziri et al' studied ACKD in 22 renal transplant recipients, including 19 cases at autopsy and three cases at bilateral nephrectomy. The prevalence of ACKD among them was 50%. Patients with ACKD received significant longer duration of dialysis and had shorter life of the functional renal allograft than those without ACKD. They concluded that the presence of a functioning renal allograft may retard the evolution of cystic changes in the native kidneys. However, persistent ACKD after renal transplantation has been reported in two autopsy cases,20 and in one patient by CT scan 63 months after transplantation. 21 More recently, Ishikawa et al lS monitored 61 renal allograft recipients with good function using CT scan for 5.3 ± 2.4 years. The prevalence of ACKD in this series was approximately 40%. Eleven patients (18%) showed an increase in cyst number, and one of them developed a RCC. This prospective study indicates that cystic transformation in the native kidneys can continue after restoration of kidney function by transplantation. In conclusion, our case represents the longest reported interval between transplantation and diagnosis of ACKD-associated RCC. ACKD may regress or progress after a successful renal transplantation. Most of the reported cases of ACKDassociated RCC after transplantation are middleaged men with a long posttransplant course, good graft function, and usage of azathioprine and prednisone as immunosuppressive agents. Male gender may be an important predisposing factor for ACKD-associated RCC in transplant patients. Be-
715
POSTTRANSPLANT RENAL CELL CARCINOMA
cause of the aggressiveness of the ACKD-associated RCC in transplant recipients, we suggest that pretransplant evaluations should include routine renal ultrasound or CT scan to detect ACKD and
ACKD-associated tumors. Last, transplant patients with flank pain, hematuria, or other suspicious symptoms should be evaluated with CT scan or sonography of their native kidneys.
REFERENCES I. Dunnill MS, Millard PR, Ogiver D: Acquired cystic disease of the kidneys: A hazard of long-term intermittent maintenance hemodialysis. J Clin Pathol 30:868-877, 1977 2. Fayemi AO, Ali M: The pathology of end-stage renal disease in hemodialysis patients. Isr J Med Sci 15:901-909, 1979 3. Gardner KD, Evan AP: Cystic kidney: An enigma evolves. Am J Kidney Dis 3:403-413, 1984 4. Hughson MD, Buchwald D, Fox M: Renal neoplasia and acquired cystic kidney disease in patients receiving longterm dialysis. Arch Pathol Lab Med 110:592-60 I, 1986 5. Port FK, Ragheb NE, Schwartz AG, et al: Neoplasms in dialysis patients: A population-based study. Am J Kidney Dis 14:119-123, 1989 6. Ishikawa I, Yuri T, Kitada H, et al: Regression of acquired cystic disease of the kidney after successful renal transplantation. Am J NephroI3:310-314, 1983 7. Vaziri ND, Darwish R, Martin DC, et al: Acquired renal cystic disease in renal transplant recipients. Nephron 37:203205, 1984 8. Ishikawa I, Saito Y, Shikura N, et al: Ten-year prospective study on the development of renal cell carcinoma in dialysis patients. Am J Kidney Dis 16:452-458, 1990 9. Arias M, de Francisco ALM, Ruiz L, et al: Acquired renal cystic disease and renal adenocarcinoma in a long term renal transplant patient. Int J Artif Organs 9:271-272, 1986 10. Faber M, Kupin W: Renal cell carcinoma and acquired cyst kidney disease after renal transplantation. Lancet I: 1030, 1987 II. Ludmerer KM, Kissane JM: Clinicopathologic con-
ference: Anew chest mass in a 49-year-old man with a transplant kidney. Am J Med 84:121-128,1988 12. Ishikawa I, Ishii H, Shinoda A, et al: Renal cell carcinoma of the native kidneys after renal transplantationA case report and review of the literature. Nephron 58:354358, 1991 13. Almirall J, Ricart MJ, Camistol 1M, et al: Renal cell carcinoma and acquired cystic kidney disease after kidney transplantation. Transplant Int 3:49, 1990 14. Penn I: Cancers following cyclosporine therapy. Transplantation 43:32-35, 1987 15. Ishikawa I, Shikura N, Shinoda A: Cystic transformation in native kidney in renal allograft recipients with longstanding good function. The II th International congress of Nephrology, Tokyo, Japan, 1990, p 151A 16. Birkeland SA: Cancers in transplant patients-The Scandia transplant material. Transplant Proc 15: 1071-1078, 1983 17. Penn I, Brunson ME: Cancers after cyclosporine therapy. Transplant Proc 20:885-892, 1988 18. Dlugosz BA, Bretan PN, Novick AC, et al: Causes of death in kidney transplant recipients: 1970 to present. Transplant Proc 21 :2168-2170, 1989 19. Yoshimura N, Oka T, Ohmaori Y, et al: A kidney transplant recipient with renal cell carcinoma derived from a native kidney. Jpn J Surg 18:208-212, 1988 20. Krempien B, Ritz E: Acquired cystic transformation of the kidneys ofhaemodialysed patients. Virchows Arch [A] 386: 189-200, 1980 21. Bommer J, Waldherr R, van Kaick G , et al: Acquired renal cysts in uremic patients-In vivo demonstration by computed tomography. Clin Nephrol 14:299-303, 1980
~ N INCREASED prevalence of renal tumors ftin patients with acquired cystic kidney disease (ACKD) associated with chronic dialysis has long been recognized. l -4 A recent populationbased study by Port et al shows a fivefold increase of invasive renal cell carcinoma (RCC) in this setting as compared with the general population. 5 Ishikawa et al6 observed regression of ACKD after successful renal transplantation. Vaziri et aC suggested that the presence of a functioning renal graft may retard the evolution of cystic changes in the native kidneys. However, we describe here a case of metastatic RCC associated with ACKD discovered 15 years after successful renal transplantation. This case represents the longest interval between transplantation and diagnosis of ACKD-associated RCC in the literature and indicates that the malignant potential of ACKD remains even after many years of normal renal function. CASE REPORT A 44-year-old white man with end-stage renal disease due to chronic glomerulonephritis received a cadaveric renal allograft in April 1974, 5 weeks after initiation of hemodialysis. The allograft was rejected within I month. He was treated with pulse steroid therapy (methylprednisolone I g every day for four doses) and local irradiation (150 rad every other day for three doses) without success. The rejected kidney was removed and replaced by another cadaveric renal graft in June 1974. He received a 2-week course of antilymphocyte globulin postoperatively, and did not have any episodes of acute rejection after the second transplantation. In May 1989, 15 years after the second renal transplantation, he presented with a nodule on the right shoulder, which had increased in size over several months. He had normal renal function and was taking
prednisone 10 mg/d, azathioprine 50 mg/d, furosemide 40 mg/d, captopril 50 mg/d for hypertension, and allopurinol 200 mg/d to prevent recurrent gout. He denied weight loss. The patient appeared healthy and had a blood pressure 130/90 mm Hg, and a pulse rate of 76 bpm. A mass with violaceous discoloration of the skin, approximately 4 cm in diameter, was palpable on the right shoulder anteriorly. Otherwise, physical examination was unremarkable. He had no lymphadenopathy or hepatosplenomegaly. Laboratory studies included hematocrit, 51.8% (hematocrit had been fluctuated between 44.1 % and 54.3% since 1975); white blood cell count, 7,800/mm 3, with neutrophil 84%, lymphocyte 10%, and monocyte 6%; serum sodium, 138 mmol/L (mEq/L); potassium, 3.7 mmol/L; CI, 107 mmol/L; CO 2 , 23 mmol/L; blood urea nitrogen (BUN), 6. 1 mmolfL urea (17 mgjdL); creatinine, 97 I'mol/L (1.1 mgjdL); Ca, 2.4 mmol/L (9.6 mg/dL); phosphate, 0.94 mmoljL (2.9 mgjdL); albumin, 40 gIL (4.0 gjdL); aspartate aminotransferase (AST), 94 IU/L; alkaline phosphatase, 200 IU/L. Urinalysis showed no proteinuria or hematuria. Chest x-ray showed clear lung fields without lymphadenopathy. An excision biopsy of the right shoulder nodule was performed and showed clear cell carcinoma (Fig lA). This finding prompted a computed tomography (CT) scan of the abdomen with contrast medium (Fig 2), which showed a 7 X 7 Xcm 5 lobular mass with low-density areas in the left kidney. The right kidney was atrophic and measured 3 X 3 X cm 4 with several 3- to 5-mm cysts and calcification. No evidence of From the Departments of Medicine, Pathology, Surgery, and Pediatrics, University ofColorado H ealth Sciences Center, Denver, CO. Y-H.H.L. is supported by a National Kidney FoundationBurroughs Wellcome Fellowship Award. Address reprint requests to Yeong-Hau H. Lien, MD, PhD, Department of Internal Medicine, Section of Renal Disease, University ofArizona, Tucson, AZ 85724. © 1991 by the National Kidney Foundation, 1nc. 0272-6386/ 9 J/ J806-00 J5$3.00/ 0
American Journal of Kidney Diseases, Vol XVIII, No 6 (December), 1991: pp 711-715
711
712
LIEN ET AL
Fig 1. Histopathology of (A) right shoulder mass, and (B, C, D) the left kidney (H&E; original magnifications: A, X 85; B, X 85; C, X 175; D, X 35). (A) Metastatic RCC in skin. Subcutaneous connective tissue is shown in the upper left corner. (B) RCC in the upper left corner and atrophic renal tissue with microcystic changes on the right side. (C) RCC, clear cell type in high-power view. (D) Invasion of RCC to renal vein.
filling defect in the left renal vein or the inferior vena cava was found. The renal allograft and the liver were normal. He underwent a left nephrectomy on May 25, 1989. The removed kidney measured 8 X 6 X 5 cm and had a markedly nodular surface. The tumor was multinodular and yelloworange, with focal areas of interlacing gray apparent connective tissue. The tumor obliterated renal architecture, invaded to the left renal vein, and extended through the renal capsule into perirenal fat. Microscopic examinations showed many microcysts in the atrophic renal tissue adjacent to the tumor (Fig IB). The cysts were lined by flat to cuboidal epithelium. Tumor cells were large and round to polygonal, with clear cytoplasm and moderately pleomorphic nuclei, consistent with clear cell carcinoma (Fig I C). Tumor invasion of renal vein was demonstrated microscopically (Fig ID). The patient did not receive chemotherapy and remained on immunosuppression. Subsequently, serial CT and a magnetic resonance imaging (MRI) scans performed 3 to 6 months after nephrectomy showed mUltiple pulmonary nodules, a small hepatic lesion, several subcutaneous lesions, and a lytic bone lesion in the right iliac bone.
DISCUSSION
We describe here a case of metastatic RCC associated with ACKD in the presence of a functioning renal graft for 15 years. The primary tumor and ACKD were discovered only after excision of a subcutaneous metastasis. The association of ACKD with chronic hemodialysis was first recognized by Dunnill et al. l ACKD occurs in 30% to 90% of dialysis patients and the prevalence increases with the duration of dialysis. The association of renal tumor with ACKD has also been recognized. I •4 Based on a review of the literature, Gardner and Evan3 calculated a prevalence of 25% for renal tumor and of 4.5% of RCC per se in dialysis patients with ACKD. More recently, Port et al 5 have reported a fivefold increase of invasive RCC in dialysis
713
POSTTRANSPLANT RENAL CELL CARCINOMA
Fig 2.
with age ranging from 39 to 58 years. Men also predominate in dialysis patients with ACKD associated RCC with a male to female ratio of 3.8: 1.4 Male gender may be a predisposing factor for the development ofRCC in patients with ACKD. The primary renal disease was chronic glomerulonephritis in five and malignant hypertension in one case. The duration of dialysis before transplantation was in the range of2 months to 5 years and duration of transplant was 2 to 15 years. Our patient had the shortest duration of dialysis and the longest duration of renal transplant. Interestingly, five of six patients had renal transplant for more than 5 years at the time of diagnosis of RCC. All of the patients had good graft function. The immunosuppression therapy was known to be azathioprine and prednisone in six cases. Two ofthese patients presented with flank pain. One presented with back pain and fever. One presented with a pulmonary nodule 3 years after removal of a "renal cell adenoma" incidentally during bilateral nephrectomy for recurrent urinary tract infection. Our patient presented with a subcutaneous nodule. The last patient was asymptomatic and RCC was diagnosed because he was followed regularly by CT scan of the native kidneys after transplantation. 12 Judging from the available data, all of these reported cases had malignant RCC because the tumors were large or multifocal, or had metastases. Four cases had documented metastases of RCC and one had a rupture of the tumor. Interestingly, the case re-
Abdominal CT scan with contrast shows a 7
x 7 x 5 cm lobular mass with low-density areas in the
left kidney. The right kidney is atrophic and measured 3 x 3 x 4 cm, with several 3- to 5-mm cysts and calcification.
patients compared with the general population in metropolitan Detroit. In Japan, a recent 10year prospective study by Ishikawa et al 8 has shown that ACKD progresses in dialysis patients and the incidence of RCC in these patients is 57 to 134 times higher than in general population. It is clear that the risk of RCC increases significantly in dialysis patients with ACKD. The association ofRCC and ACKD in renal transplant recipients has not been well addressed. Table I lists the reported cases of well-documented ACKD and renal tumors in renal transplant recipients, including the present case. 7 ,9.I3 Among them, six cases have adequate clinical information for analysis. All six of these cases are men,
Table 1. Reported Cases of ACKD Associated Renal Tumors in Renal Transplant Recipients Primary Aenal Author
Vaziri'
Age/Sex
Disease
Duration of Dialysis/AT
Graft Function
NA 46/M
NA CGN
NA 5 yr'/5yr
NA Good
45/M
HTN
3 yr/2 yr
Good
49/M
CGN
10 mo/ll
Ishikawa'2
39/M
CGN
Almirall'3
58/M
Present case
44/M
Arias' Faber10
Ludmerer
11
..
Immunosuppresskln AZA/PAED NA AZA/PRED
Presentation NA Flank pain, hematuria Flank pain
Mu~ifocal RCC 7 ·cm RCC with rupture
0.5· to Ik:m ACC, bilateral, Met: lymph nodes/lungs 2 ACC, one 2.4 cm, no met 7·cm ReC, Met: bones/lungs Ik:m RCe, renal vein invasion, Met: skin/ bones~iver/Iungs
RCC, Met: lymph nodes~ungs/bones
So. ~
1.6
AZA/PRED
Pulmonary nodules
8 mo/8 yr
So. ~
1.3·1.6
AZA/PRED
Asymptomatic
CGN
5 yr/7yr
Sc. ~
1.1
AZA/PRED
Back pain, fever
CGN
2 mo/15 yr
So. ~
1.1
AZA/PRED
Subcutaneous nodule
yr
Pathological Findings
, Duration of dialysis prior to transplantation. Abbreviations: RT, renal transplant; CGN, chronic glomerulonephritis; HTN, hypertension; AZA, azathioprine; PRED, prednisone; RCe, renal cell carcinoma; S"" serum creatinine (in mg/dL); Met, metastases; NA, not available.
714
ported by Ishikawa et al l2 had a slow growing RCC, which was retrospectively found by CT scan (1.2 cm in size) taken 7 years before the diagnosis of RCC. A series of CT scans showed that the growth of the tumor was parallel to the progression of ACKD. The clinical course of this case was similar to the ACKD-associated renal adenomas in dialysis patients. Penn 14 reported a case of "epithelioma" in a transplant patient under cyclosporine therapy. The tumor was incidentally discovered in the wall of a renal cyst. 14 This case is not included in Table 1, because ACKD was not documented. In the two largest series of transplant recipients with ACKD, one case of RCC was found in each, but no benign renal tumors were reported histologically in 11 cases? and radiographically in 26 cases. IS Whether the presence of ACKD increases the risk of developing RCC in renal transplant recipients is unclear. Earlier, in a Scandinavian series,16 four of 112 malignancies encountered in 3,956 renal transplant recipients from 1969 to 1978 were RCC, with three involving native kidneys and one involving the allograft. The prevalence ofRCC of native kidneys in this study was 0.08%. More recently, Penn and Brunson 17 reported that the frequency of RCC as de novo malignancies following cyclosporine therapy was 23 of 412 tumors, with 22 involving native kidneys and one involving allograft. The investigators suggested that the high frequency of RCC may be related to ACKD; however, whether ACKD was present was not mentioned in this study. Dlugosz et al lS reported that metastatic RCC of native kidneys accounted for 2% of deaths in 222 renal transplant recipients over an 18-year period. They also suggested that the incidence of RCC may be higher in these patients. Since most reports of ACKD-associated RCC do not indicate a population at risk, it is difficult to estimate the incidence ofRCC in renal transplant recipients with ACKD. In a prospective study by Ishikawa et al, one of 26 renal transplant recipients with ACKD developed RCC. IS However, it could be a chance occurrence. The low reported rate of ACKD-associated RCC may be due to the lack of recognition of the association ofRCC with ACKD in transplant patients, long induction time of RCC from renal cysts, and difficulty in diagnosis of RCC in native atrophic kidneys.
LIEN ET AL
Yoshimura et al l9 reported a case of metastatic RCC of the spine and liver 4 years after transplantation. A small primary RCC in a native kidney was only identified at autopsy. We believe that once the association between ACKD and RCC is recognized, more cases of ACKD-associated RCC in transplant patients will be discovered in the future. Our patient had ACKD despite good renal graft function 15 years after transplantation. The effect of restoration of renal function by renal transplantation on ACKD has been addressed. Ishikawa et al6 reported resolution of acquired cysts with shrinking of native kidneys in two of three patients 8 to 10 months after successful renal transplantation. The third patient had incomplete involution of the cysts. Vaziri et al' studied ACKD in 22 renal transplant recipients, including 19 cases at autopsy and three cases at bilateral nephrectomy. The prevalence of ACKD among them was 50%. Patients with ACKD received significant longer duration of dialysis and had shorter life of the functional renal allograft than those without ACKD. They concluded that the presence of a functioning renal allograft may retard the evolution of cystic changes in the native kidneys. However, persistent ACKD after renal transplantation has been reported in two autopsy cases,20 and in one patient by CT scan 63 months after transplantation. 21 More recently, Ishikawa et al lS monitored 61 renal allograft recipients with good function using CT scan for 5.3 ± 2.4 years. The prevalence of ACKD in this series was approximately 40%. Eleven patients (18%) showed an increase in cyst number, and one of them developed a RCC. This prospective study indicates that cystic transformation in the native kidneys can continue after restoration of kidney function by transplantation. In conclusion, our case represents the longest reported interval between transplantation and diagnosis of ACKD-associated RCC. ACKD may regress or progress after a successful renal transplantation. Most of the reported cases of ACKDassociated RCC after transplantation are middleaged men with a long posttransplant course, good graft function, and usage of azathioprine and prednisone as immunosuppressive agents. Male gender may be an important predisposing factor for ACKD-associated RCC in transplant patients. Be-
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cause of the aggressiveness of the ACKD-associated RCC in transplant recipients, we suggest that pretransplant evaluations should include routine renal ultrasound or CT scan to detect ACKD and
ACKD-associated tumors. Last, transplant patients with flank pain, hematuria, or other suspicious symptoms should be evaluated with CT scan or sonography of their native kidneys.
REFERENCES I. Dunnill MS, Millard PR, Ogiver D: Acquired cystic disease of the kidneys: A hazard of long-term intermittent maintenance hemodialysis. J Clin Pathol 30:868-877, 1977 2. Fayemi AO, Ali M: The pathology of end-stage renal disease in hemodialysis patients. Isr J Med Sci 15:901-909, 1979 3. Gardner KD, Evan AP: Cystic kidney: An enigma evolves. Am J Kidney Dis 3:403-413, 1984 4. Hughson MD, Buchwald D, Fox M: Renal neoplasia and acquired cystic kidney disease in patients receiving longterm dialysis. Arch Pathol Lab Med 110:592-60 I, 1986 5. Port FK, Ragheb NE, Schwartz AG, et al: Neoplasms in dialysis patients: A population-based study. Am J Kidney Dis 14:119-123, 1989 6. Ishikawa I, Yuri T, Kitada H, et al: Regression of acquired cystic disease of the kidney after successful renal transplantation. Am J NephroI3:310-314, 1983 7. Vaziri ND, Darwish R, Martin DC, et al: Acquired renal cystic disease in renal transplant recipients. Nephron 37:203205, 1984 8. Ishikawa I, Saito Y, Shikura N, et al: Ten-year prospective study on the development of renal cell carcinoma in dialysis patients. Am J Kidney Dis 16:452-458, 1990 9. Arias M, de Francisco ALM, Ruiz L, et al: Acquired renal cystic disease and renal adenocarcinoma in a long term renal transplant patient. Int J Artif Organs 9:271-272, 1986 10. Faber M, Kupin W: Renal cell carcinoma and acquired cyst kidney disease after renal transplantation. Lancet I: 1030, 1987 II. Ludmerer KM, Kissane JM: Clinicopathologic con-
ference: Anew chest mass in a 49-year-old man with a transplant kidney. Am J Med 84:121-128,1988 12. Ishikawa I, Ishii H, Shinoda A, et al: Renal cell carcinoma of the native kidneys after renal transplantationA case report and review of the literature. Nephron 58:354358, 1991 13. Almirall J, Ricart MJ, Camistol 1M, et al: Renal cell carcinoma and acquired cystic kidney disease after kidney transplantation. Transplant Int 3:49, 1990 14. Penn I: Cancers following cyclosporine therapy. Transplantation 43:32-35, 1987 15. Ishikawa I, Shikura N, Shinoda A: Cystic transformation in native kidney in renal allograft recipients with longstanding good function. The II th International congress of Nephrology, Tokyo, Japan, 1990, p 151A 16. Birkeland SA: Cancers in transplant patients-The Scandia transplant material. Transplant Proc 15: 1071-1078, 1983 17. Penn I, Brunson ME: Cancers after cyclosporine therapy. Transplant Proc 20:885-892, 1988 18. Dlugosz BA, Bretan PN, Novick AC, et al: Causes of death in kidney transplant recipients: 1970 to present. Transplant Proc 21 :2168-2170, 1989 19. Yoshimura N, Oka T, Ohmaori Y, et al: A kidney transplant recipient with renal cell carcinoma derived from a native kidney. Jpn J Surg 18:208-212, 1988 20. Krempien B, Ritz E: Acquired cystic transformation of the kidneys ofhaemodialysed patients. Virchows Arch [A] 386: 189-200, 1980 21. Bommer J, Waldherr R, van Kaick G , et al: Acquired renal cysts in uremic patients-In vivo demonstration by computed tomography. Clin Nephrol 14:299-303, 1980
