Jack H Mydlo and Matthew Karlovsky

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Department of Urology, Temple University School of Medicine, Philadelphia, PA, USA

The American Cancer Society has recently stated that one out of five Americans will develop cancer in his or her lifetime. In addition, for those patients who develop a tumor, there is a one out of three chance of developing a second tumor in their lifetime. This suggests that there may be an underlying problem with the person's immune surveillance system, or something inherently wrong with their genetic self-regulation and/or tumor suppressor genes.1'2 Within the sample of patients who have more than one cancer in their lifetime, there is a subset of patients who present for the diagnosis and treatment of one tumor, and a second primary tumor is detected during the work-up of the first primary tumor. Multiple primary malignancies are defined as those tumors that present themselves as distinct primary entities, and are themselves not metastases of the other lesion.3

This finding of two simultaneous primary tumors is a particularly unusual and sometimes difficult dilemma. Treatment will usually be initially determined by the more aggressive lesion, age and medical condition of the patient.4

Among the secondary tumors that occur with a higher incidence in cancer patients are melanoma and lung cancer, and lymphoma and renal cell carcinoma.5'6 Greenberg etal. reported an increased incidence of bladder cancer in those patients with prostate cancer.7 Liskow etal. also reported an increase in bladder cancer in those patients with prostate cancer. They also found an increase in lymphoma in these patients as well.8 However, Kawakami etal. found no increase in multiple primary malignancies in prostate cancer patients,9 which has also been shown by Isaacs etal.10 Furthermore, in a large Swiss study by Levi etal. examining 4503 cases, they actually found a reduced incidence of neoplasms in men who were diagnosed with prostate cancer. In addition, they did not find an association between cigarette smoking and prostate cancer.11

Brenner etal. reported a small but statistically significant risk of developing secondary tumors, most commonly bladder cancer, after radiotherapy for prostate cancer. This was especially noted in the earlier days of radiation therapy, prior to today's more focused radiotherapy ports.12

In a retrospective chart review of 2339 patients with prostate cancer, Moyer etal. reported 222 on patients (9.5%) who developed a second primary malignancy. Sixty-nine of these 222 patients (31%) presented with a synchronous lesion, while the other 153 patients presented with metachronous lesions.13 They found that, of the 153 patients with metachronous lesions, 86 (56%) were diagnosed with prostate cancer first before their other tumor, whereas 67 (44%) were diagnosed with prostate cancer after the diagnosis of a prior primary tumor. When stratified among race, the most common second malignancies among Whites with localized prostate cancer were bladder and colon cancer. However, when stratified for stage, bladder cancer was much more common in Whites with localized prostate cancer, whereas colon cancer was more common in Whites with metastatic prostate cancer. In Black patients with localized prostate cancer, they found a greater incidence of colon and bladder cancers; for those with metastatic disease, they found a greater incidence of lung cancer. These findings were statistically significant with regard to observed versus expected cases of multiple malignancies, both in the general population, and when stratified by race.11 Also, second primary malignancies were more likely to be detected in White patients.

Overall, White patients developed more cases of colon and bladder carcinoma while Black patients developed more cases of lung carcinoma. With respect to race and prostate cancer stage in their study, Whites with localized and metastatic disease were more likely to develop bladder and colon carcinoma, respectively, while Blacks were more likely to develop bladder and colon carcinoma when localized and lung carcinoma when metastatic, suggesting different risks depending upon patient race and stage of prostate cancer.

Moyer et al. concluded that Black patients were more likely to present with metastatic disease compared to Whites. Also, when prostate cancer was diagnosed first, a statistically significant increase was seen in the number of colon, bladder and kidney cancers. However, when race was considered, they discovered a statistically significant increase in the number of colon and bladder cancer cases in Whites, and lung and esophageal cases in Blacks. Their data suggested that patient race and initial stage of prostate cancer may influence the likelihood and site of a second primary malignancy.13

Various other studies have found the incidence of multiple primary tumors in prostate cancer patients to range from 11.5% in a series by Liskow etal.8 to 20% in a series by Lynch etal.14 and even to 27% in autopsy series by Hadju and Hadju.15 The exact etiology of this incidence is uncertain. It may be related to the overall increased awareness of prostate cancer in the general population, and the medical community, especially since the advent of prostate specific antigen (PSA) screening. The earlier diagnosis of prostate cancer has led to its detection prior to any potential development of a second malignancy.

Considering race and the detection of a second primary malignancy, the data of Moyer et al. also revealed that 147 out of 1240 (11.9%) of White patients had a second primary detected, while only 69 out of 1035 (6.7%) of Blacks patients had detection of a second primary.13 This contradicts several previous studies. The study by Hadju and Hadju noted a higher incidence of second primary malignancies in Blacks over Whites.15 Studies by Liskow8 and Paulish16 found a similar incidence of second primaries in both Blacks (approx. 11%) and Whites (approx. 11%). The etiology behind this difference between races is not known. One possible cause could have been that certain factors (dietary, environmental, genetic) were present in the White population and not in the Black population.17 Another possible reason could have been that the White patients underwent better and longer follow-up compared to the Black patients. Also, smoking may be more common among certain Black populations than their White cohorts.

Another possible reason that certain studies have demonstrated more aggressive tumors in Blacks than Whites, or more metastatic lesions, may be at the hormonal and molecular level. This has been reported by Mydlo et al., who demonstrated a greater expression of mutant p53 expression, higher levels of serum testosterone and a higher incidence of positive pathologic margins in Black patients versus White patients with prostate cancer.18'19 Adding to the notion of increased aggressive tumor behavior may have been the relative decreased prostate cancer awareness earlier on in the Black community. The percentage of advanced prostate cancer might have been decreased, if these patients underwent earlier routine screening.

As mentioned previously, one of the main reasons for the increased detection of prostate cancer, either as a primary tumor, or as a secondary tumor, has been the use of increased PSA testing. However, along with the increased utilization of sonography, computed tomography (CT) scanning and magnetic resonance of patients, it may be possible to detect secondary or multiple tumors in cancer patients, either at initial presentation or at follow-up.12 In addition, because the specialist may focus more closely on the involved organ system, it is reasonable to expect the urologist to detect prostate cancer and synchronous bladder or renal cancers with an increased frequency, or the gynecologist to detect cervical and ovarian cancers with increased frequency. The detection of other primary malig nancies outside the organ system of specialty concern may also be 'unmasked' during preoperative evaluation.

Mydlo et al. described patients with urological cancers and malignancies of non-urologic origin.4 Over a 6-year period, 515 patients were evaluated for a urological malignancy. Twenty-three (4.3%) were found to have multiple tumors. Three of these patients had concomitant prostate and bladder cancer. One developed bladder cancer after external-beam radiotherapy for his prostate cancer.

It is important to note that those patients with multiple primary malignancies had been categorized differently from those patients who developed second primaries as a result of chemotherapy and/or radiotherapy of the primary tumor.20,21 This would include those patients who develop bladder cancer years after they had treatment for prostate cancer by external beam radiation therapy. The other 19 patients (3.5%) were found to also have a non-urological primary malignancy.

Thirteen patients were found to have a second primary malignancy during the work-up of their urological tumor. All the prostate cancer patients were diagnosed after scanning PSA's were elevated. All the renal tumor patients had their tumors detected from a hematuria work-up, except for one. This one patient had her renal tumor detected incidentally during her colon cancer work-up (Fig. 6.1a,b). One bladder cancer patient had her colon tumor diagnosed from a preopera-tive CT scan. The other urological cancer patients had gynecological tumors detected by physical examination, CT examination and cervical cytology preparations. Four prostate cancer patients had heme-positive stools; this led to a diagnosis of colon cancer. The last patient had renal cancer as well (patient 19, Table 6.1).

In the study by Mydlo etal., one patient was referred who was previously diagnosed with two primary malignancies (gastric cancer was detected first and then his prostate cancer was detected from a screening PSA). Another patient with prostate cancer had a lung mass detected on his preoperative chest X-ray, which revealed primary adenocarcinoma of the lung. After undergoing a successful wedge resection, the patient underwent a radical retropubic prostatectomy without incident. Another prostate cancer patient was treated for his prostate tumor and had a sigmoid tumor resection simultaneously. The latter was detected during a digital rectal examination for his prostate, which was positive for occult blood (Table 6.1).

While some surgeons may be reluctant to combine such complicated surgeries together, which would overlie suture lines, these patients were found to have no more complications than the general population.4

Many patients with presumed localized prostate cancer in the USA with PSA values below 10 do not undergo nuclear bone scans or abdominal CT scans, especially if surgery is planned. This is because numerous studies have demonstrated the low incidence of positive bone scans for PSA levels below this value. However, for those patients undergoing either brachytherapy or external beam radiation therapy, these imaging modalities may be used for volume assessment of the gland and may, therefore, detect additional pathology.20

Fig. 6.1. (a) A 63-year-old male (patient # 19) underwent a prostate examination for an elevated PSA. His stool was positive for occult blood and a barium enema revealed an 'apple core' lesion, consistent with colon cancer. Further work-up with a CT scan revealed a large right renal tumor. (b) His colon and renal tumors were resected first in one operation, and then the patient underwent subsequent brachytherapy for his prostate cancer.

Fig. 6.1. (a) A 63-year-old male (patient # 19) underwent a prostate examination for an elevated PSA. His stool was positive for occult blood and a barium enema revealed an 'apple core' lesion, consistent with colon cancer. Further work-up with a CT scan revealed a large right renal tumor. (b) His colon and renal tumors were resected first in one operation, and then the patient underwent subsequent brachytherapy for his prostate cancer.

However, Miller et al. reported a low incidence of coexistent disease in pretreatment CT scanning for radiation therapy in patients with prostate carcinoma.20 Only two patients out of 77 patients (3%) had any major abnormalities that required intervention, and these were not tumors. Nakata etal. analyzed the clinical features of multiple primary cancers, which included prostate cancer. They found an incidence of 15.2% of multiple primary malignancies in their review. The organ most commonly involved was the stomach, followed by the bladder, colon and lungs.21

Other reports described the incidental pathological findings of prostate cancer along with bladder cancer after radical cystoprostatectomies. Moutzouris etal. reported a 27% incidence of finding prostate cancer in cystectomy specimens. These secondary tumors occurred most likely at the apex.22

Cannon etal. reported on the increased occurrence of primary cancers in association with multiple myeloma and Kaposi's sarcoma.23 With the advent of effective pharmacotherapy for erectile dysfunction in the elderly, there is speculation that there may be a corresponding increase in the incidence of sexually transmitted diseases among this age group, including the human immunodeficiency virus, or HIV.24 This may have many ramifications in the future in the treatment of patients with prostate cancer.

Hepatitis C has been considered a high-risk factor for secondary primary malignancies besides hepatocellular carcinoma.

Table 6.1. Nineteen patients with urologie cancer and another primary malignancy. Reprinted from Urology, Vol. 58, Mydlo and Gerstein, Urologie cancer patients with another primary malignancy, pp. 243-7. Copyright (2001), with permission from Elsevier Science.

Patient

Age/Sex

Urologic tumor

Treatment

Stage

Other tumor

Treament

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