Late Age (≥85 Years) Peak Incidence of Urinary Bladder Cancer

Abstract

Urinary bladder cancer is classically considered to be caused by industrial exposure and tobacco use; however the usual causative factors in this type of cancer fail to explain the peak age-specific incidence in the age 85–95 group. The peak is observed consistently with both sexes and bridges ethnicity. This late peak in age of onset has significance in health care delivery and financing, as well as in research in to the causes of bladder cancer.

INTRODUCTION

In the United States, urinary bladder cancer (UBC) is expected to be responsible for 67,160 new cancer cases and approximately 13,750 deaths in 2007 [1]. Multiple factors have been correlated with UBC: environmental carcinogens, lifestyle, and genetic predisposition.

Industrial exposures to carcinogen has been identified as the major cause of UBC [2]. A study by Brown et al. found that industrial exposure to respirable crystalline silica increases the occurrence of UBC, while showing no consistent relationship between exposure and lung cancer [3]. Another study by Kogevinas et al. concluded that metal workers, machinists, transport equipment operators and miners were among the major occupational classifications (1 in 10–20 UBC cases) with elevated incidence of UBC among men in Western Europe [4].

Findings by Vallanueva et al. did not prove that ingestion of fluids (tap water and coffee) led to the cancer, but strengthened the hypothesis that environmentally influenced carcinogens in such fluids could explain the increase in cancer rates [5].

Lifestyle factors have also been correlated with increased incidence of UBC. In addition to tobacco, other carcinogens have been correlated with UBC. A study by Gan et al., determined that diverse exposure to arylamines in non-smokers is strongly associated with bladder cancer risk and may account for the vast majority of bladder cancers. Additionally, a Los Angeles bladder cancer study found that women who used permanent hair dyes were at a greater risk for UBC, possibly due to its arylamine content, [6].

The p27^Kip1 and p53 pathways are believed to be important in UBC occurrence. Rabbani et al. studied the prognostic significance of p27^Kip1 expression in UBC found that low expression of p27^Kip1 was a significant independent predictor of pelvic recurrence, progression to metastasis, death from the disease, and death from any cause in patients with UBC [7].

Additionally, it was concluded by Sanchez-Carbayo et al. that a single nucleotide polymorphism (SNP309) was frequent in UBC and related to early onset of superficial UBC as well as T53 mutation status. UBC tumors are known to commonly contain TP53 mutations and less frequently HDM2 (a transcriptional target gene of p53) amplifications [8].

In 1988, cancer was legislated to be a reportable disease in California to create a large sample of cancer data for scientific analysis. The California Cancer Registry (CCR) became the repository for the data. This study examines the CCR’s UBC related data.

MATERIALS AND METHODS

New cases are reported to the CCR by physicians, health facilities, laboratories, etc., with penalties for failure to report cases. The actual abstracting of cases is done by Certified Tumor Registrars. Ten Regional Cancer Registries act as the first-level receiving facility and provide quality assurance, coordination of multiple reports for the same patient, technical help to those reporting cases, and then report the data to the central registry in Sacramento. At this level, there is further quality assurance, elimination of duplicate entries, clearance with death certificates, and mutual referrals of reports of patients actually residing in other states. The CCR is certified by the North American Association of Central Cancer Registries (NAACCR) and the entire state is currently part of NCI’s Surveillance, Epidemiology, and End Result (SEER) Program.

The CCR is the population-based registry serving the largest population (36 million in 2004), and probably the most diverse in the world. Seventeen years of data (2,387,316 individual cancers), with all patient, physician, and institutional identification removed, are available to researchers. This includes 92,677 cases of urinary bladder cancer (in-situ and invasive) from 1988 through 2004. In addition to patient demographics, features of the tumor such as stage, histology, and follow-up information are available.

The abstracting process includes review of reports of tissue examination (Surgical Pathology, Cytology, Bone Marrow, Autopsy, etc.). From these reports, invasive cancer was separated from in-situ cancer; the invasive cases are the basis of this report. All cases were included in one or the other of these two categories. Since carcinoma-in-situ can be recognized only on microscopic examination, all of these cases had such an examination. 97.8% of the invasive cases had microscopic examination, and the rest were diagnosed on the basis of clinical examination, radiologic procedures, autopsy gross examination, death certificates, etc. Most of the 2.2% of invasive cases without tissue examination were cases located by death certificate clearance only.

The 55,159 cases of invasive UBC in the CCR from 1988 to 2004 form the basis of this report. Of these cases, 83.2% (45,865) were non-Hispanic White, 4.0% (2,231) were African-American, 7.7% (4,250) were Hispanic, 4.2% (2,317) were Asian/Pacific Islander, and 0.9% (517) was of other unknown ethnicity. Additionally, 74.1% (40,909) were male and 25.9% (14,271) were female. 47,871 (86.8%) were of transitional cell type. While both age-specific and age-adjusted rates are calculated for various ethnic, histologic, and gender groups, only the age-specific rates were used for this manuscript.

Although peaking slightly younger than invasive UBC, in-situ UBS also shows a peak incidence at a later age than most in-situ cancers [9].

Median ages for both genders and for all four ethnic groups ranged from 67.75 to 71.77 years. While there are “statistically significant” differences, these are undoubtedly a result of the very large numbers used in the sample and have little, if any, practical significance.

RESULTS

Data from the California Cancer Registry (CCR) show a universal peak in age-specific incidence of UBC among men and women over 85 years of age, with a higher incidence in males (Figure I).

Figure I.

These data differ from those data for age-specific incidence rates of lung and bronchus cancer, where the peak incidence age was in the 75–79 age group (Figure II). The lung and bronchus data in Figure II show a steep reduction in the incidence of lung and bronchus cancer at ≥85 years of age (Figure II). When compared to the age-specific incidence rates of all invasive cancers, a similar trend is followed with a peak age of incidence in the ≥ 85 years of age group (Figure III). This peak in incidence is further demonstrated by the increasing annual percent of UBC cases in patients 85 and older (Figure IV). The percent of UBC in people over 85 (slope = .395) is increasing about ten times as fast as the percent of the population over 85 (slope = .0336) over the 17 years (Figure IV). In contrast, the trend line for the population virtually overlies the line of the population itself.

Figure II.

Figure III.

Figure IV.

This peak incidence effect seen in all of those ≥ 85 years of age is also illustrated across ethnic boundaries (Figure V). The White population has the highest incidence of UBC with roughly one-third greater incidence rate of African Americans, the group with the next highest incidence population. Additionally, there is a drastic drop in UBC incidence in all groups at age 95–99. Only the Asian cohort continues to decline past this age group, while the other ethnic groups rebound after that point (Figure V). The rise in age-specific incidence at age 100, in most groups is felt to be a reflection of the small numbers in this age group.

Figure V.

Histologically, the majority of the cases (0.4%) are of transitional cell type in nature, followed by epidermoid (squamous cell) (2.4%) and adenocarcinoma (2.0%) (******Figure VI). Transitional cell carcinoma arises in the transitional epithelium lining of the bladder, while adenocarcinoma is assumed to originate in glandular tissue. Epidermoid carcinoma is an aggressive tumor with a poor prognosis and short survival period for the patient; some consider these to be very dedifferentiated transitional cell carcinomas. Magnification of the scale in Figure VI shows that the epidermoid carcinoma shows the same late peak as transitional cell carcinoma, but adenocarcinoma does not, supporting the concept stated just previously.

Figure VI.

Finally, in Table I, it can be seen that the proportion of patients with UBC, age 85 and older is about ten times that of the total population, and about twice that of patients with other cancer, regardless of sex. For comparison, data for lung/bronchus and prostate cancer are shown.

DISCUSSION

Data obtained by the CCR were vital in detecting the unique peak incidence of UBC in people ≥85 [9]. This is 20 years after the general retirement age and implies a longer than usual latent period in carcinogenesis. Comparing Figure I to Figure II, there is a 10 year peak difference between lung/bronchus cancer and UBC. This is notable as both lung and bladder cancers share some of the same carcinogens: tobacco and industrial exposure. This disparity could be due to a variety of reasons. The lungs are the first organs to come into contact with the various carcinogens, whereas the bladder receives these carcinogens last and presumably in a more diluted state than the lungs. By the time they reach the bladder, these carcinogens may have lost much of their potency. Hence the bladder may require longer exposure for the induction of cellular mutations by carcinogens. This would explain the latent peak in UBC among the ≥ 85 years of age group as opposed to lung cancer group, where the carcinogens have direct and full potency contact with the organ. (Figure I, II).

We detected no late age peak seen in the incidence of transitional cell carcinoma of the renal pelvis. This may be due to a variety of reasons, one of which may be that urine in the bladder is more concentrated than in the renal pelvis. This more concentrated urine may be more carcinogenic than the less concentrated urine found in the renal pelvis. These observations warrant further investigation.

Additionally, there is no explanation of why, compared to other causes, the incidence of UBC has become so high within both sexes, but in particular the female population. While smoking is a common occurrence in both populations, work in the industrial sector has traditionally been done by males. One explanation is a possible “Rosie the Riveter” effect on the female population. The population ≥ 85 years of age in 2004 would have been, at the youngest, born in 1919, and during the start of the US involvement in the Second World War (WWII) in 1941, women born in 1919 would have been age 21. Women of this age during that time worked heavily in the industrial sector to create goods for military and civilian usage [10]. A woman who was 21 in 1941 would be 67 in 1988 and would be 93 in 2004, making this a reasonable theoretical cohort for study. For the duration of the World War II and after, the women of the ≥ 85 years of age cohort could well have experienced hazardous industrial working conditions, which may explain the high prevalence among females of this age grouping. Additionally, inexpensive cigarettes were provided by the tobacco companies, as well as placed into meal rations (K rations) for the military [11], further propagating an increase in smoking. Unfortunately, because the CCR only has data on patients whose UBC was first diagnosed between 1988 and 2004, it is not possible to do more than speculate on this theory.

If the “Rosie the Riveter” theory is correct then the subsequent generation, the “Baby Boomers,” might show a subsequent decline in the rates of UBC in women. However, this hypothesis may be found to be false due to the increases in rates of smoking in women after WWII and continued industrial exposure [12]. Additionally, it is hypothesized that there will be increased incidence rates of UBC in women of the current working generation due to increasing numbers of women serving in the military. These hypotheses require further cohort studies.

Finally, while tobacco use and industrial exposure are known carcinogens involved in lung/bronchus cancer and UBC, it is unknown if there is a particular carcinogen in the industrial sector that primarily affects the bladder, while having no influence on lung/bronchus cancer. More research on identifying particular carcinogens that affect the transitional epithelium of the bladder will be important in the progression of UBC clinical care.

CONCLUSION

The percent of patients with UBC who are 85 and older is increasing with time much faster than either that fraction of the population or patients with other cancers. This observed trend has implications for the delivery of medical care and its financing. In addition, it may give new clues to the causes of urinary bladder cancer. Currently there is no published research explaining why the peak incidence of bladder cancer is in the population ≥ 85 years of age. We know of no clinical trials in participants from among the oldest age groups. Given the increasing rates of UBC among the 85 and older population, it will be critical to encourage investigators to study this age group as they continue to search for causative factors and genetic contributors to UBC, as well as to develop more effective treatments.

Table I.

Percent of Group Age 85 or Older

Group	Female	Male	Both Sexes
Bladder	16.7%	10.1%	11.8%
All invasive cancer except Bladder	7.9%	5.8%	6.9%
Total Population without cancer	1.6%	0.7%	1.2%
Lung/Bronchus invasive cancer	7.0%	5.6%	6.2%
Prostate invasive cancer	--	5.7%	--

ABBREVIATIONS

CCR

California Cancer Registry

NAACCR

North American Association of Central Cancer Registries

NCI

National Cancer Institute

SEER

Surveillance, Epidemiology, and End Result

SNP309

Single Nucleotide Polymorphism

UBC

Urinary Bladder Cancer