Aristolochic acid-containing Chinese herbal medicine and upper urinary tract urothelial carcinoma in Taiwan: a narrative review.

PURPOSE: The high incidence of upper urinary tract urothelial carcinoma (UTUC) in Taiwan is largely due to exposure to aristolochic acid (AA), a principal component of Aristolochia-based herbal medicines. Here we systematically review the molecular epidemiology, clinical presentation and biomarkers associated with AA-induced UTUC. METHODS: This is a narrative review. Medline, Embase, and Web of Science were searched from inception to December 31, 2021. Studies evaluating the association, detection, and clinical characteristics of AA and UTUC were included. RESULTS: A nationwide database revealed 39% of the Taiwanese population had been exposed to AA-containing herbs between 1997 and 2003. Epidemiological reports revealed AA posed a significantly higher hazard for renal failure and UTUC in herbalists and the general population who ingested AA-containing herbs. The presence of aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, located predominantly on the non-transcribed DNA strand, with a strong preference for deoxyadenosine in a consensus sequence (CAG), was observed in many UTUC patients. Clinically, AA-related UTUC patients were characterized by a younger age, female gender, impaired renal function and recurrence of contralateral UTUC. To date, there are no preventive measures, except prophylactic nephrectomy, for subjects at risk of AA nephropathy or AA-related UTUC. CONCLUSION: AA exposure via Aristolochia-based herbal medicines is a problem throughout Taiwan, resulting in a high incidence of UTUC. Aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, can be used as biomarkers to identify AA-related UTUC. AA-related UTUC is associated with a high recurrence rate of contralateral UTUC.

Comparative analysis of patients with upper urinary tract urothelial carcinoma in black-foot disease endemic and non-endemic area.

BACKGROUND: A high incidence of upper urinary tract urothelial carcinoma has been reported in the southwestern area of Taiwan, where arsenic water contamination was considered the main cause. However, there is no definite proof to show a correlation between arsenic water contamination and upper urinary tract urothelial carcinoma. To investigate the clinical and epidemiological features of patients with upper urinary tract urothelial carcinoma between arsenic water endemic and non-endemic areas, we analyzed patients in terms of characteristics, stratified overall survival, disease-free survival, and cancer-specific survival. METHODS: The records of a total of 1194 patients diagnosed with upper urinary tract urothelial carcinoma were retrospectively reviewed. Clinical data and current medical status were collected from the medical records. Statistical analyses were performed to determine the clinical variables and stratified survival curves between endemic and non-endemic groups. RESULTS: Female predominance was revealed in both endemic and non-endemic groups (male:female ratio = 1:1.2-1.4). No statistical differences were found in histological types, staging, and tumor size between the two groups. Nonetheless, patients with characteristics of aging and having end-stage renal disease were outnumbered in the non-endemic group, while a higher prevalence of previous bladder tumors and more ureteral tumors were found in the endemic group. Adjusted stratified cumulative survival curves suggested a poorer prognosis in endemic patients, especially in disease-free survival of early stage disease. CONCLUSIONS: A higher mortality rate with more previous bladder cancer history and ureteral tumors was seen in patients with upper urinary tract urothelial carcinoma residing in the arsenic water contamination area. This may be attributed to the long-term carcinogenic effect of arsenic underground water.

Long-Term Lithium Use and Risk of Renal and Upper Urinary Tract Cancers.

Lithium induces proliferation in the epithelium of renal collecting ducts. A recent small-scale cohort study reported a strong association between use of lithium and increased risk of renal neoplasia. We therefore conducted a large-scale pharmacoepidemiologic study of the association between long-term use of lithium and risk of upper urinary tract cancer, including renal cell cancer and cancers of the renal pelvis or ureter. We identified all histologically verified upper urinary tract cancer cases in Denmark between 2000 and 2012 from the Danish Cancer Registry. A total of 6477 cases were matched by age and sex to 259,080 cancer-free controls. Data on lithium use from 1995 to 2012 were obtained from the Danish Prescription Registry. We estimated the association between long-term use of lithium (≥5 years) and risk of upper urinary tract cancer using conditional logistic regression with adjustment for potential confounders. Long-term use of lithium was observed among 0.22% of cases and 0.17% of controls. This yielded an overall nonsignificant adjusted odds ratio (OR) of 1.3 (95% confidence interval [95% CI], 0.8-2.2) for upper urinary tract cancer associated with long-term use of lithium. Analyses stratified by stage and subtype of upper urinary tract cancer revealed slight but nonsignificant increases in the ORs for localized disease (OR, 1.6; 95% CI, 0.8-3.0) and for renal pelvis/ureter cancers (OR, 1.7; 95% CI, 0.5-5.4). In conclusion, in our nationwide case-control study, use of lithium was not associated with an increased risk of upper urinary tract cancer.

Aristolochic acid-associated urothelial cancer in Taiwan.

Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of (5')AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.

Urethral carcinoma and hyperplasia in male and female B6C3F1 mice treated with 3,3',4,4'-tetrachloroazobenzene (TCAB).

B6C3F1 mice chronically exposed to 3,3',4,4'-tetrachloroazobenzene (TCAB), a contaminant of dichloroaniline-derived herbicides, developed a number of neoplastic and nonneoplastic lesions, including carcinoma of the urinary tract. Groups of fifty male and fifty female B6C3F1 mice were exposed by gavage to TCAB at dose levels of 0, 3, 10, and 30 mg/kg five days a week for two years. Control animals received corn oil:acetone (99:1) vehicle. Decreased survival of male mice in the mid-dose group and of male and female mice in the high-dose groups was related mainly to the occurrence of urethral transitional cell (urothelial) carcinoma and resulting urinary obstruction. Increased urethral transitional cell carcinomas were seen in all treated male groups in a dose-related manner as well as in the females treated with 30 mg/kg TCAB. Administration of TCAB was also associated with increased transitional cell hyperplasia of the urethra. Most nonneoplastic lesions of the urogenital tract were considered secondary to local invasion and urinary obstruction by the urethral transitional cell carcinomas. The mechanism of tumor induction is uncertain, but the high frequency of tumors in the proximal urethra of male mice suggests that the neoplasms result from the exposure of a susceptible population of urothelial cells to a carcinogenic metabolite of TCAB.

[Sporadic upper urinary tract urothelial cell carcinomas: identification of interaction between toxic carcinogens and individuals genetic susceptibility]. / Tumeurs des voies excrétrices urinaires supérieures sporadiques: identification de l'interaction entre l'exposition aux carcinogènes environnementaux et la susceptibilité génétique des individus.

Upper urinary tract urothelial cell carcinomas (UUT UCC) are rare sporadic tumors. Recent epidemiologic and molecular data have shown a singular susceptibility of UUT UCCs for specific risk factors. The main exogenic factors involved in UUT UCCs carcinogenesis remain tobacco and occupational exposure (aromatic amines, polycyclic hydrocarbures and chlored solvents). Enzymatic variants of detoxification system may be responsible of carcinogenesis with these toxics. Tumors induced by phenacetine consumption are decreasing since it was banned in the 1970s. Also, acid aristolochic exposure (Balkan nephropathy, Chinese Herb nephropathy) has been demonstrated to specifically induce UUT UCCs. Familial genic polymorphism of detoxification system would explain geographic distribution in endemic areas. In Taiwan, chronic arsenic exposition would constitute the main risk factor of UUT UCC. However, theses mechanisms of carcinogenesis remain unclear. The knowledge of UUT UCC development mechanisms implying toxic detoxification systems is still incomplete. To date, there is a growing body of evidence supporting that the interaction between individual genetic susceptibilities and environmental toxic exposure is a key to explain carcinogenesis in the majority of sporadic UUT UCC occurrence.

Balkan Endemic Nephropathy and the Causative Role of Aristolochic Acid.

Balkan endemic nephropathy is a chronic tubulointerstitial disease with insidious onset, slowly progressing to end-stage renal disease and frequently associated with urothelial carcinoma of the upper urinary tract (UTUC). It was described in South-East Europe at the Balkan peninsula in rural areas around tributaries of the Danube River. After decades of intensive investigation, the causative factor was identified as the environmental phytotoxin aristolochic acid (AA) contained in Aristolochia clematitis, a common plant growing in wheat fields that was ingested through home-baked bread. AA initially was involved in the outbreak of cases of rapidly progressive renal fibrosis reported in Belgium after intake of root extracts of Aristolochia fangchi imported from China. A high prevalence of UTUC was found in these patients. The common molecular link between Balkan and Belgian nephropathy cases was the detection of aristolactam-DNA adducts in renal tissue and UTUC. These adducts are not only biomarkers of prior exposure to AA, but they also trigger urothelial malignancy by inducing specific mutations (A:T to T:A transversion) in critical genes of carcinogenesis, including the tumor-suppressor TP53. Such mutational signatures are found in other cases worldwide, particularly in Taiwan, highlighting the general public health issue of AA exposure by traditional phytotherapies.

First experimental demonstration of the multipotential carcinogenic effects of aspartame administered in the feed to Sprague-Dawley rats.

The Cesare Maltoni Cancer Research Center of the European Ramazzini Foundation has conducted a long-term bioassay on aspartame (APM), a widely used artificial sweetener. APM was administered with feed to 8-week-old Sprague-Dawley rats (100-150/sex/group), at concentrations of 100,000, 50,000, 10,000, 2,000, 400, 80, or 0 ppm. The treatment lasted until natural death, at which time all deceased animals underwent complete necropsy. Histopathologic evaluation of all pathologic lesions and of all organs and tissues collected was routinely performed on each animal of all experimental groups. The results of the study show for the first time that APM, in our experimental conditions, causes a) an increased incidence of malignant-tumor-bearing animals with a positive significant trend in males (p < or = 0.05) and in females (p < or = 0.01), in particular those females treated at 50,000 ppm (p < or = 0.01); b) an increase in lymphomas and leukemias with a positive significant trend in both males (p < or = 0.05) and females (p < or = 0.01), in particular in females treated at doses of 100,000 (p < or = 0.01), 50,000 (p < or = 0.01), 10,000 (p < or = 0.05), 2,000 (p < or = 0.05), or 400 ppm (p < or = 0.01); c) a statistically significant increased incidence, with a positive significant trend (p < or = 0.01), of transitional cell carcinomas of the renal pelvis and ureter and their precursors (dysplasias) in females treated at 100,000 (p < or = 0.01), 50,000 (p < or = 0.01), 10,000 (p < or = 0.01), 2,000 (p < or = 0.05), or 400 ppm (p < or = 0.05); and d) an increased incidence of malignant schwannomas of peripheral nerves with a positive trend (p < or = 0.05) in males. The results of this mega-experiment indicate that APM is a multipotential carcinogenic agent, even at a daily dose of 20 mg/kg body weight, much less than the current acceptable daily intake. On the basis of these results, a reevaluation of the present guidelines on the use and consumption of APM is urgent and cannot be delayed.

Analgesics, cigarette smoking, and other risk factors for cancer of the renal pelvis and ureter.

Results from a population-based case-control study of cancer of the renal pelvis and ureter are reported. Telephone interviews were conducted with 187 residents of Los Angeles County diagnosed with cancer of the renal pelvis and ureter over a 4-year period ending December 31, 1982, and with individually sex-, age- and race-matched neighborhood controls. The major risk factor identified for cancer of the renal pelvis and ureter was cigarette smoking. Subjects who smoked more than 25 years had a relative risk of 4.5 of developing these tumors, compared to nonsmokers (P less than 0.0001). Heavy use of over-the-counter analgesics was also associated with a significant increase in risk; it appears that an elevated risk was conveyed by all the major active constituents of those compounds currently marketed in the United States, aspirin, caffeine, and acetaminophen. Persons who had used these drugs for 30 consecutive days at any time in their life preceding diagnosis had twice the risk of developing cancer of the renal pelvis or ureter compared to persons not reporting such use (P less than 0.01). Heavy coffee drinkers (greater than or equal to 7 cups/day) had a 1.8-fold increase in risk compared to nondrinkers. Although risk tended to increase with increasing consumption, this result was not statistically significant. The risk associated with heavy coffee consumption was reduced to 1.3 after adjusting for smoking. Nine cases compared to no controls reported a first degree relative with kidney cancer. A history of kidney stones was associated with an increased risk of cancer of the ureter (relative risk = 2.5) that was not, however, statistically significant.

Ureteral Metastasis: Uncommon Manifestation in Prostate Cancer.

Ureteral metastasis from a primary prostate cancer is a rare event in the initial diagnosis and progression of prostate cancer. We report here the case of a 72- year-old patient who was treated for castration-resistant metastatic prostate cancer involving bone, intra-abdominal lymph nodes, bilateral adrenal glands, and a small distal ureteral lesion with left hydronephrosis considered in remission, with a luteinizing hormone-releasing hormone analog plus abiraterone acetate (AA) and prednisone after initial docetaxel plus prednisone chemotherapy. After an episode of acute left flank pain, the previous left distal intraluminal ureteral mass appeared increased in volume on computed tomographic scan and was compatible with either a metastasis from prostate cancer, transitional cell carcinoma of the ureter, or a collision tumor. After left nephroureterectomy (NU), the mass was confirmed to be of prostatic origin on histopathological examination and the only site of metastatic progression of prostate cancer. Abdominal CT-scan and the operative specimen of the NU showed no direct extension of the abdominal lymph nodes into the ureteral lesion. We speculate that this unique ureteral prostate cancer metastasis was the result of hematogenic spread of prostate cancer, although microscopic spread through the lymphatic system could not be excluded. The transient anti-tumor effect of AA plus prednisone at the level of ureteral metastasis, as far as we are aware of, has never been documented before.

Urothelial lesions in Chinese-herb nephropathy.

Rapidly progressive renal fibrosis after a slimming regimen including Chinese herbs containing aristolochic acid (AA) has been identified as Chinese-herb nephropathy (CHN). We reported urothelial atypia in three patients with CHN, with the subsequent development in one patient of overt transitional cell carcinoma (TCC). Therefore, it was decided to remove the native kidneys, as well as the ureters, in all patients with CHN. Nineteen kidneys and ureters removed during and/or after renal transplantation from 10 patients were studied to assess critically urothelial lesions and to characterize the cellular expression of p53, a tumor-suppressor gene overexpressed in several types of malignancies. Multifocal high-grade flat TCC in situ (carcinoma in situ; CiS) was observed, mainly in the upper urinary tract, in four patients, a prevalence of 40%. In one of those patients, a superficially invasive flat TCC of the right upper ureter, as well as two additional foci of noninvasive papillary TCC, were found in the right pelvis and left lower ureter, respectively. This patient also presented recurrent noninvasive papillary TCC of the bladder. Furthermore, in all cases, multifocal, overall moderate atypia was found in the medullary collecting ducts, pelvis, and ureter. All CiS and papillary TCC, as well as urothelial atypia, overexpressed p53. These results show that the intake of Chinese herbs containing AA has a dramatic carcinogenic effect. Carcinogenesis is associated with the overexpression of p53, which suggests a role for a p53 gene mutation. The relationship of this mutation with the reported presence of AA DNA adducts in the kidney remains to be explored.

[Analgesics and laxatives as risk factors for cancer in the efferent urinary tract--results of the Berlin Urothelial Carcinoma Study]. / Analgetika und Laxantien als Risikofaktoren für Krebs der ableitenden Harnwege--Ergebnisse der Berliner Urothelkarzinom-Studie (BUS).

A retrospective case-control study (1990-1995), the Berlin Urothelial Cancer Study (BUS), examined analgesics and laxatives as risks for the induction of urothelial cancer in renal pelvis, ureter and bladder. Especially for renal pelvis cancer could observe substance and dose specific risk of compound analgesics. The analgesic substances Phenacetin, Paracetamol, Acetylsalicylic acid (ASA) and Pyrazolones were assessed. Besides a risk of contact laxatives (chemical or anthranoide ingredients) for urothelial cancer was found, not yet described. The highest risk shows the anthranoide plant Senna. Thus this study confirms the risk of specific analgesic ingredients and found an evidence for a new risk of contact laxatives. As both, analgesics and contact laxatives, are typical OTC--("Over the counter") products, a severe controlling is demanded and for laxatives further studies are needed.

[Causes and consequences of long term consumption of phenacetin-containing analgesics, from the urologist's point of view (author's transl)]. / Ursachen und Folgen langjähriger Einnahme phenacetinhältiger Analgetika aus der Sicht des Urologen.

In the last two decades reports concerning analgesic nephropathies have been presented from most industrial countries. Today, there is no doubt concerning a causal association between long-term consumption of analgesics and renal failure. In a group of 274 urological patients, the reasons and consequences of long-term intake of phenacetin-containing compounds are herewith demonstrated. The reason for chronic consumption of analgesics is mainly headache, due to psychosomatic causes which had not been adequately treated. After an average latency period of 20 years, renal (papillary necrosis, chronic interstitial nephritis) and extrarenal manifestations appeared. Despite slow progression and low gradient symptoms, severe alterations could be determined at the first examination. Course and prognosis primarily depend on a successful cessation of analgesics and the elimination of the accompanying infection. In the last decade, an increase of transitional cell carcinoma induced by analgesics has been observed. 22 of our patients presented a tumor of the urothelium (i.e. 8%). A further increase of these specific cases is expected.

[Carcinoma of the ureter after long-term use of analgesic [phenacetin derivative]--report of the two cases (spouses)].

Two cases (spouses) of carcinoma of the ureter possibly induced by long-term use of analgesic were presented. Case 1: A 66-year-old female with hematuria was diagnosed as a carcinoma of the ureter in January, 1985 and underwent resection of the left kidney and the ureter with partial resection of the urinary bladder. In December, 1988 she died due to recurrent cancer. Case 2: A 70-year-old male (a husband of case 1 patient) with hematuria was diagnosed as a carcinoma of the ureter in August, 1987 and underwent resection of the kidney and the ureter of the left side. In October, 1988 he died due to recurrent cancer. These two patients had used routinely phenacetin because of persistent headache for about 20 and 15 years, respectively and the presumed total dose was amounted to 4 and 2.5 kg, respectively.