Urologia Internationalis
Urol Int 2004;72:168-170 DOI: 10.1159/000075974
Received: August 13, 2001 Accepted after revision: May 6, 2002
Unusual Double Primary Neoplasia: Adrenocortical and Ureteral Carcinomas in Werner Syndrome
Ryoji Takazawaa Junichi Ajimaª Akimasa Yamauchia Makoto Gotob
Departments of ªUrology and bRheumatic Diseases, Tokyo Metropolitan Otsuka Hospital, Tokyo, Japan
Key Words
Werner syndrome . Double primary neoplasia · Adrenocortical carcinoma . Ureteral carcinoma
Abstract
Adrenocortical and ureteral carcinomas were observed in a 50-year-old Japanese woman with Werner syn- drome (MIM No. 27770). The syndrome is an autosomal recessive disorder characterized by premature aging and an increased risk of rare cancers, which are often multi- ple. This is the first reported association of adrenocorti- cal carcinoma in Werner syndrome.
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Case Report
A 50-year-old woman presented with a 6-month history of hyper- tension (BP 170/76 mm Hg), hyperglycemia (FBS 144 mg/dl), and pitting edema on both hands and feet. She was diagnosed as having Werner syndrome (WS) by several progeroid manifestations and by two immunological methods: detection of the failure of WS gene pro- tein production by Western blotting [1], and mutant allele specific amplification method [2]. She had a 6/6 mutation. She had 2 daugh- ters, and her parents were first cousins. She had a bird-like face and a stocky trunk with extremely thin limbs, which are characteristic of WS [3]. Blood examination revealed hypokalemia (1.9 mEq/l), ele- vated serum cortisol level (24.4 ug/ml) and a reduced serum ACTH level (6 pg/ml). Urine examination showed an elevated excretion of 17-OHCS (12.3 mg/day). CT scans showed a 12 × 10 x 10 cm mass
in the right adrenal gland, which compressed the liver and the vena cava (fig. 1a). Moreover, a right hydronephroureter was found (fig. 1b). Retrograde pyelouretrography and urinary cytology re- vealed an obstruction of the ureter by another tumor, which was sus- pected to be a transitional cell carcinoma. Our diagnosis was right adrenal tumor and right ureteral tumor. Due to the size, the adrenal tumor was suspected to be a cortical carcinoma, causing Cushing syn- drome. Both tumors were resected. The adrenal tumor weighed 150 g, and had a variegated yellow or brown appearance. Hemor- rhage and partition were seen on cross-section (fig. 2a). Histological- ly, the adrenal tumor cells grew in a fascicular or diffuse pattern. Broad fibrous bands intersecting the tumor, vascular invasion, nu- clear hyperchromasia and atypical mitoses were found. Clear cells constituted about 25% of the cell population (fig. 2b). Necrosis was not found. From the Hough and Weiss criteria [4], the adrenal tumor was diagnosed as a cortical carcinoma, not adenoma. The adrenal tumor cell was positive for vimentin, synaptophysin and partially positive for cytokeratin, but negative for EMA, PAS, S-100 in immu- nohistochemical studies. The presence of synaptophysin protein in the tumor cell may show evidence of neuroendocrine differentiation [4]. A papillary tumor in the right upper ureter caused hydronephro- sis (fig. 2c). Histology of the tumor suggested a transitional cell carci- noma (fig. 2d), which invaded the surrounding tissues diffusely and metastasized to the pelvic lymph nodes. The ureteral tumor cells was positive for EMA, cytokeratin, but negative for PAS, S-100 and vimentin. The symptoms of Cushing syndrome improved 10 days after surgery. The patient was given external irradiation to the right retroperitoneum (40 Gy in 20 fractions over 28 days) and chemother- apy (Tegafur 300 mg, daily). One month after surgery, however, she developed local recurrence of the right adrenal carcinoma and multi- ple metastases to the liver, followed by the return of Cushing syn- drome. The patient died 5 months after diagnosis. The family declined autopsy.
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Discussion
WS is an autosomal recessive disorder characterized by premature aging, more commonly reported in Japan than elsewhere because of the high rate of inbreeding there. The gene, RecQ type DNA helicase, is mapped to chromosome 8p 11.1-12.1 [5, 6]. Death on average is at 46 years, due mainly to arteriosclerosis or cancer [3]. Var- ious types of neoplasia are associated with WS [7], most often thyroid carcinoma, acral lentiginous melanoma, os- teosarcoma and other soft-tissue sarcomas. To the best of our knowledge, there have been previous reports of 3 tran- sitional cell carcinomas, 1 renal cell carcinoma and 1 sem- inoma in WS [7]. Two or more of these neoplasms oc- curred in the same patient [7]. Among hereditary cancer syndromes, Li-Fraumeni syndrome (MIM No. 151623) in which germline mutations of p53 or Chk2 are found, is prone to adrenocortical carcinoma (and in common with WS, osteosarcoma and soft-tissue sarcomas) [8, 9]. The adrenal neoplasia occurs in childhood, however. An ex- cess of this tumor has been observed in Carney’s com- plex (MIM No. 160980), Beckwith-Wiedemann syn- drome (MIM No. 130650), hemihypertrophy (MIM No.
235000), multiple endocrine neoplasm, type I (MIM No. 131100), and adrenocortical carcinoma, hereditary (MIM No. 202300). The possible contribution of the genetic instability caused by the mutation of DNA helicases in some premature aging syndromes including WS (DNA helicase disease) to tumorgenesis is proposed [6]. The patient did not have predisposing factors of urothelial car- cinoma, such as heavy smoking, habitual use of phenace- tin-containing analgesics, or occupation using some spe- cific chemical materials [10]. Adrenocortical carcinoma is linked mainly to genetic disorders but not to environmen- tal exposure. On the other hand, urothelial carcinoma is linked mainly to environmental exposure (including ciga- rette smoking). Urothelial carcinoma occurs in WS, but adrenocortical carcinoma has not been reported before this case [7]. Pending reports of additional cases, the con- currence is due either to the pathophysiology of WS or to chance.
Acknowledgement
We would like to thank Dr. Robert W. Miller at the National Cancer Institute for his kind discussions.
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Copyright: S. Karger AG, Basel 2004. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.
Copyright: S. Karger AG, Basel 2004. Reproduced with the permission of S. Karger AG, Basel. Further reproduction or distribution (electronic or otherwise) is prohibited without permission from the copyright holder.