Giant Hydronephrosis Due to a Ureteral Stone

å¡ CASE REPORT å¡

Giant Hydronephrosis due to a Ureteral Stone, and Elevated Serum Levels of CA 19-9 Ryushi Shudo, Tetsuya Saito, Kuniyasu Takahashi, Kazutoshi Horita, Katsuaki Waku*, Ichiya Honma** and Takashi Sato**

CA19-9 is a widely used tumor marker. However, an elevation in serum CA19-9 can occur in somepatients with benign disorders such as cholecystolithiasis in the absence of tumor. Wetreated a case of acquired ureteral stone-induced giant hydronephrosis with markedly elevated serum CA19-9 values. After nephrectomy, the serum CA19-9 level returned to normal. No malignant cells were found in the tissues of the resected kidney. Localization of CA19-9 was confirmed by immunohistochemical staining of the renal pelvic mucosa. A detailed case report is presented with a review of the literature. (Internal Medicine 38: 887-891, 1999) Key words: tumor marker, benign disorder, immunohistochemical staining

Introduction markable. Onadmission, the results of blood count, blood bio- chemical studies and urinalysis were within normal limits. The Hydronephrosisresults fromthe obstruction and stasis of tumor marker CA19-9 level was markedly elevated (2,500 U/ urinary flow, which is nowa relatively commondisorder en- ml) (Table 2). Plain abdominal radiography showed a radio- countered by physicians in daily practice because of the ad- paque shadow (10x18 mm) located in the L 3-4 intervertebral vances in ultrasonography. However, "giant hydronephrosis", area, which appeared to be a calcified stone. Computed tomog- a kidney containing more than 1,000 ml of fluid in its collect- raphy (CT) scan of the abdomen revealed a huge cystic lobu- ing system, is uncommon.The serum level of the tumor marker lated mass in the left kidney and occupying the left intraperito- CA19-9 is knownto be elevated in patients with gastrointesti- neal and pelvic cavities. The distention of the left kidney renal tumors, especially, pancreatic carcinoma. In the field of sulted in the thinning of the parenchyma. The cystic mass ex- urology, increased serum CA 19-9 levels have been reported in tended beyond the median line, with a shadow indicative of a patients with pyeloureteral tumors; however, to our knowledge, calcific stone visualized in the same site as depicted on the only 6 cases of the benign disorder, hydronephrosis, including plain abdominal film (Fig. 1). The calcific body was seen on the present case, were reported to have significant elevations the right side of the vertebral bodies because of the advanced of the marker. Of these, in 5 cases (including the present case) stage of hydronephrosis. No abnormalities were found in the the localization of CA1 9-9 was proved immunohistochemically other organs examined, including the liver, gall bladder and through staining of CA19-9 (Table 1) (1-5). pancreas. Excretory urography revealed no significant excretion from the left kidney, indicating the lack of renal function. For editorial comment, see also p 840. Urine cytology provided no signs of abnormality. Based on the findings from diagnostic imaging, cytology and other examinations, the patient was diagnosed as having giant left hydro- Case Report nephrosis, attributable to a left ureteral stone, with lack of left renal function. In September 1997, left nephrectomy was per- A42-year-old womanexperienced a sensation of left flank formed in the light of the risk that the thinning of the renal distention beginning around July 1997 and came to our hospi- parenchyma would cause rupture of the kidney and because of tal for consultation on August 7, 1997. Since an elastic hard the severe abdominal distention due to the enlarged left kid- mass and slight tenderness were noted in the left flank, she ney. An oblique incision was madein the left pelvic region, was admitted for detailed examination. Past history was unre- reaching the retroperitoneal cavity. A huge hydronephrotic kid- From the Department of Internal Medicine, *Surgery, Shizunai Municipal Hospital, Shizunai and * *the Department of Urology, Oji General Hospital, Tomakomai Received for publication January 28, 1999; Accepted for publication June 1 9, 1999 Reprint requests should be addressed to Dr. Ryushi Shudo, the Department of Internal Medicine, Shizunai Municipal Hospital, 5-1, 4 street, Midori-cho, Shizunai, Hokkaido 056-0004

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Table 1. Reported Cases of Giant Hydronephrosis with Elevated Serum Levels of CA19-9 F lu id Ca se R ef . n o. Y ea r A ge /S ex S ym pt om L oc at io n C au se c ol le c ti on C A 1 9- 9 Tr ea t me nt P at ho l og y Im m un oh is to ch e mi ca l ( m l ) ( U / m l ) s t a i n i n g o f C A 1 9 - 9

(1) 199 2 6 8/M ab d .flatu len ce righ t ston e n .m . 19 57 nephrostom y b enign po sitive 2. (2 ) 199 4 74 /F fever righ t sto ne n .m . l,00 0< op e b enign po sitive 3. (3 ) 199 5 7 6/M urinary reten tion left ston e n .m . 2,340 op e b enign neg ativ e 4. (4 ) 199 5 4 5/M ab d . flatu len ce left ston e 1,50 0 9 60 op e b enign p o sitive 5. (5 ) 199 6 60 /F ab d . p ain left vu s n .m . 5 80 op e b enign p o sitive 6 . P r e s e n t c a s e 1 9 9 8 4 2 / F a b d . f l a t u l e n c e l e f t s t o n e 2 , 0 0 0 2 , 5 0 0 o p e b e n i g n p o s i t i v e

Ref. no.: reference number, M: male, F: female, abd: abdominal, vus: vesicoureteral stricture, n.m.: not mentioned, ope: operation.

Table 2. Laboratory Data on Admission H em atolog y T otal ch olestero l 163 mg/dl Red blood cell count 40 1x 104/u l T rig lyceride 66 mg/dl H em og lo bin ll.3 g/dl Blood urea nitrogen 15 mg/dl H em ato crit 34 .1% C reatinine 0.7 mg/dl White blood cell count 7,700/ul S od iu m 139 mEq// P latelet co u nt 36.6x l O4/ul P otassiu m 3.9 mEq/l Chl oride 10 4 mEq/l Blood chemistry Fasting blood sugar 82 mg/dl T otal pro tein 7.1 g/d l A m y lase 5 1 IU // A lbu m in 4.2 g/dl T otal bilirub in 0.5 mg/dl U rin aly sis Direct bilirubin 0.2 mg/dl P rotein (-) Zinc sulfate turbidity test 9 . O U Su gar (-) Thymol turbidity test 2 . 6 U Occult blood (-) Aspartate aminotransferase 15 IU // Alanine aminotransferase 8 TU // Tumo r mar kers Lactate dehydrogenase 36 5 IU // C E A <1.0 ng/ml Alkaline phosphatase 12 1 TU // CA 1 9- 9 2,500 U/ml Y-G lu tam yltran sp eptid ase 8 IU // Choline esterase 4,503 IU/1 24-hour Creatinine clearance 12 7.1 //d ay

ney was exposed. The hydronephrotic sac was drained by suc- tion of its contents through a small incision and it wasablated from adjacent tissues. Then, left nephrectomy was performed. By aspiration, approximately 2,000 ml of fluid was removed. The cross-section of the resected kidney showedmarked pyelocaliectasis, and a pale yellow stone was present in the ureteropelvic junction (UPJ) (Fig. 2A). Chronic interstitial inflammation wasobserved extending into the mucosaof the renal pelvis, parenchyma and ureter. The thin renal parenchyma, showing significant fibrosis, retained only sparse tubules among

Figure 1. Abdominal computed tomography revealed a huge cystic lobulated mass in the left kidney occupying the left intra- peritoneal region. Distention of the left kidney resulted in the thinning of the parenchyma. The cystic mass extended beyond the median line, with a shadow indicative of a calcific stone (arrow).

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Figure 3. Immunohistochemical staining of CA 19-9 showed positive reactions at various sites in the epithelium of the ureteropelvic junction (x80).

Discussion Hydronephrosis is the distention of the pelvis and calyces of the kidney due to the obstruction and stasis of urinary flow caused by a lesion in the upper or lower tract. The disorder is relatively commonly found in everyday practice. However, "giant hydronephrosis", defined by Stirling (6) to designate the presence of 1,000 ml or more fluid in the collecting system, is rare, with only 373 cases reported so far in Japan ac- cording to the review by Morimitsu et al (7). Most cases of giant hydronephrosis result from the devel- opment of a lesion in the upper urinary tract, which is thought to be because a lesion of lower tract origin, often bilateral, tends to cause a reduction in renal function in the early stage of the Figure 2. Histopathological findings. (A) Cross-section of the process, producing various subjective/objective manifestations, resected kidney showing marked pyelocaliectasis, and a pale yel- and is thus frequently detected before the hydronephrotic kid- low stone (10x18 mm)(arrow) was present in the ureteropelvic ney grows into a giant mass. It has been reported that 47 of the junction. (B) Chronic interstitial inflammation was observed ex- 49 cases could be attributed to upper tract lesions (7). Morimitsu tending into the mucosa of the renal pelvis. The thin renal pa- et al (7) reported that an abnormality in the UPJ was the most renchyma, showing significant fibrosis, retained only sparse tu- commoncause of giant hydronephrosis, followed by stones, bules amongthe replaced fibrous elements (HEstain, x20). congenital ureteral narrowing and ureteropelvic tumors in order of decreasing incidence. The present case was a giant hydronephrosis of the left kidney due to a ureteral stone. the replaced fibrous elements and was devoid of normal pa- Once the presence of giant hydronephrosis is known, the renchymal structure (Fig. 2B). No evidence of malignancy was important issue in treatment is howto arrive at a preoperative found. The left kidney appeared to be in the terminal stage of diagnosis of a ureteropelvic tumor associated with the disease. deterioration, having lost its function. No specific abnormali- Whenthe patient is aged 50 years or older and presents with ties were noted in the UPJ. Immunohistochemical staining of hematuria, in particular, the possible coexistence of a malig- CA19-9 by the enzyme-labeled antibody technique showed nant tumor should be considered; thus, it is preferable to con- positive reactions at various sites in the epithelium of the UPJ duct a detailed exploration of the renal pelvis and calyces by (Fig. 3). The postoperative course wasuneventful. Theserum such meansas CTscan, ultrasonography, magnetic resonance CA19-9 level has been within the normal range since discharge imaging, etc., and to perform repeated cytologic studies of the from hospital. urine. In our case, no signs indicative of malignancywerefound by repeated urinary cytology, abdominal ultrasonography, or CT scanning. The decision between nephrectomy and kidney-conserving

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therapy should be a critical issue in the management of giant patients in many countries. This phenomenon, whether derived hydronephrosis. However, in practice, nephrectomy has been from a racial difference or another cause, or purely by chance, performed in the majority of instances. Hoffman(8) stated that should be elucidated by studies in a greater number of patients. nephrectomy is frequently the only therapy for giant hydro- The mechanism of abnormal elevations in serum CA19-9 nephrosis with a capacity of or above 1,000 ml because there in patients with hydronephrosis can be explained by 1) abnor- is no feasible prospect of improvement in renal function. We mal synthesis of the antigen in sites other than the kidneys, 2) also believe that nephrectomy is the treatment of choice in prin- synthesis in the gastrointestinal organs surrounding the kidney- ciple if the function of the contralateral kidney is normal. The (s) which is induced by compression from hydronephrosis or primary reasons are that the existence of the huge hydroneph- 3) excessive synthesis in the mucosaof the renal pelvis result- rotic kidney, even when retaining some function, is likely to ing from chronic inflammation. In the present case, interpreta- cause gastrointestinal disturbances from compression and also tion 1 is unlikely because of the finding that the serum CA19- wouldbe subject to trauma. In addition, the risk of develop- 9 values decreased to the normal range by resection of the af- mentof malignant tumor due to chronic stimulation by stones, fected kidney and that no malignant tumor was found through if present, should be considered (9). Weperformed nephrec- the subsequent follow-up period. The second notion is also tomy in the present case, because no excretion of contrast me- unlikely from the findings of CT scan and ultrasonographic dium was observed on drip infusion pyelography examination examinations, which indicate a low possibility of compression and the renal parenchyma was scarcely visible by CTscan- of the pancreas, bile duct, gall bladder and other organs by the ning, strongly indicating the lack of renal function. hydronephrotic kidney. The third is the most probable hypoth- CA1 9-9 is a tumor-associated carbohydrate antigen discov- esis, as CA19-9 has been shown to be localized in the mucosa ered by Koprowski et al (10) using a monoclonal antibody of the renal pelvis by immunohistochemical staining. Thus, in against a humancolorectal carcinoma cell line. It has become our case, this also maybe considered the most probable cause widely accepted as one of the most useful tumor markers in of the elevated levels of CA19-9. The excessive production of the diagnosis and managementof cancer patients. This anti- the antigen in the renal pelvic mucosamayhave resulted from gen, monosialoganglioside, is knownto have a carbohydrate long-term, chronic inflammation secondary to hydronephrosis structure as a sialyl derivative of lacto-N-fucopentaose II, a or CA19-9 may have been synthesized in the renal pelvic mem- hapten of the human Lewis blood group antigen (ll). It is brane and released into the blood circulation by an increase in present in trace amounts in normal humanepithelia (12). How- the internal pressure of the renal pelvis due to hydronephrosis. ever, with the developmentof carcinoma, the antigen will be In any case, urinary tract obstruction that has been present over synthesized in large quantities and appear in blood and secre- a period of years appears to be implicated in a significant el- tions. CA19-9 is frequently detected in the serum of patients evation of serum CA19-9 values. with gastrointestinal carcinoma in general; it is especially el- Theutility of CA19-9 as a tumormarker for urologic carci- evated in patients with pancreatic and bile duct carcinomas in nomais nowunder evaluation. Keeping in mind that CA19-9 that order of decreasing frequency of detection ( 13). Immuno- levels mayalso increase in patients with benign disorders of histochemical assay (12) can also frequently detect CA19-9 in the renal tubules and pelvis, further accumulation of clinical the tissue of various adenocarcinomas, mainly gastrointestinal data should be conducted. Although no malignancy of the kid- carcinoma. Thus, CA19-9 is a major marker and is elevated in neys was found in the 6 patients with hydronephrosis accom- patients with hepatocellular, bile duct, pancreatic and other panied by elevations in serum CA19-9 (Table 1), it would be carcinomas. Although the CA19-9 level is knownto rise in of interest to determine whether malignant lesions develop in patients with benign disorders, there is a report (14) stating such hydronephrotic patients during the follow-up period, and, that an excessive elevation in serum CA19-9 exceeding 1,000 if so, whether a rise in serum CA19-9accompanies this pro- U/ml can be attributed to a malignant disorder in 99%of cases. cess. It is also important to knowwhether hydronephrotic pa- In the field of urology, there are also patients with ureteropel- tients with increased serum CA19-9 levels have a higher risk vic transitional cell carcinoma whoexhibit elevations in se- of developing cancer than those without such an elevation. Thus, rum CA19-9 and positive immunohistochemical staining of further studies, including those using immunohistochemical and the antigen in tumor cells (15-17). CA19-9 has been reported molecular biological approaches, appear to be needed. to be present in the tubules and pelvic mucosa of normal kidneys (18). In addition, cases of the benign disorder, hydroneph- References rosis, presenting with excessive elevations of CA19-9 have been reported ( 1-5). Amongthese hydronephrotic patients, the 1) Nakahara Y, Nakahara Y, KawanamiM, et al. A case of transient sharp localization of CA19-9 in the mucosa of the renal pelvis has elevation of blood CA19-9after percutaneous nephrostomy for hydronephrosis due to ureter stone. Iryo 46: 844-848, 1992 (in Japanese with been proved in 5 cases, including the present case, by use of English Abstract). the immunohistochemical staining technique of the antigen 2) Ito S, Nishikawa K, Goto T, Tsujita M, Takegaki Y, Kishimoto T. A case (Table 1). All 5 reported cases are Japanese cases. It is of inter- of hydronephrosis caused by renal stones with elevated serum levels of est that the abnormality in CA19-9 level in such cases has CA19-9 and CA-125. Hinyokika Kiyo (Acta Urol Jpn) 40: 885-888, 1994 been reported only in Japan despite the fact that serum CA19- (in Japanese with English Abstract). 9 is a major tumor marker determined frequently in various 3) Inoue S, Kajiwara T, Itakura H, Munakata A, Shinohara M, Kinoshita K.

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Hydronephrosis with high level CA19-9 in serum: A case report. Hinyoki 14369, 1982. Geka 8: 651-653, 1995 (in Japanese with English Abstract). 12) Atkinson BF, Ernst CS, Herlyn M, Steplewski Z, Sears HF, Koprowski 4) Kamai T, Touma T, Masuda H, Ishiwata D. A case of severe hydroneph- H. Gastrointestinal cancer-associated antigen in immunoperoxidase as- rosis with significantly elevated serum CA19-9. Rinsho Hinyokika 49: say. Cancer Res 42: 4820-4823, 1982. 855-857, 1995 (in Japanese with English Abstract). 1 3) Del Villano BC, Brennan S, Brock P, et al. Radioimmunometric assay for 5) Kondoh K, Noguchi S, Shuin T, Masuda M, Kubota Y, Hosaka M. A case a monoclonal antibody-defined tumor marker, CA19-9. Clin Chem 29: of hydronephrosis with high level of serum SPan-1 antigen and CA19-9. 549-552, 1983. Hinyokika Kiyo (Acta Urol Jpn) 42: 51-53, 1996 (in Japanese with En- 14) Steinberg W. The clinical utility of the CA19-9 tumor-associated antigen. glish Abstract). AmJ Gastroenterol 85: 350-355, 1990. 6) Stirling WC. Massive hydronephrosis complicated by hydroureter. J Urol 15) Kodama K, Sadakata H, Mitomo O, Miyao S, Shibayama K, Naruse T. 42: 520-533, 1939. CA 1 9-9 producing transitional cell carcinoma of renal pelvice and ureter. 7) Morimitsu H, Sakaguchi M, Suzu H, et al. Giant hydronephrosis: 2 case Rinsho Hinyokika 45: 1048-1050, 1991 (in Japanese with English Ab- reports and a review of 373 cases in the literature. Nishinihon J Urol 52: stract). 761-766, 1990 (in Japanese with English Abstract). 16) Nakata S, Kurokawa K, Ebihara K, Urano E, Yamanaka H, Suzuki K. A 8) Hoffman HA. Massive hydronephrosis. J Urol 59: 784-794, 1948. case of ureter tumor which showed high level of serum CA19-9. Rinsho 9) KumeH, Kojima H, Takai K. Transitional cell carcinoma of the renal Hinyokika 43: 147-150, 1989 (in Japanese with English Abstract). pelvis associated with long-standing renal calculi: a case report. Nishinihon 17) Ishii T, Iwasaki H, Kikuchi M. Immunohistochemical demonstration of J Urol 53: 732-735, 1991 (in Japanese with English Abstract). carbohydrate antigen 19-9 (CA 1 9-9) in transitional cell carcinoma of the 10) Koprowski H, Steplewski Z, Mitchell K, Herlyn M, Herlyn D, Fuhrer P. urinary tract. Igaku no ayumi 139: 419-420, 1986 (in Japanese with En- Colorectal carcinoma antigens detected by hybridoma antibodies. Somatic glish Abstract). Cell Genet 5: 957-972, 1979. 18) Ohshio G, Ogawa K, Kudo H, et al. Immunohistochemical distribution ll) Magnani JL, Nilsson B, Brockhaus M, et al. A monoclonal antibody- ofCA19-9 in normal and tumor tissues of the kidney. Urol Int 45: 1-3, defined antigen associated with gastrointestinal cancer is a ganglioside 1990. containing sialylated lacto-N-fucopentaose II. J Biol Chem 257: 14365-

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