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Cancer of the Prostate in Men Less than 50 Years Old: An Analysis of 51 Cases
Vol. 102, Dec.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright © 1969 by The Williams & Wilkins Co.
CANCER OF THE PROSTATE IN MEN LESS THAN 50 YEARS OLD: AN ANALYSIS OF 51 CASES DAVID P. BYAR
AND
F. K. MOSTOFI
From the Armed Forces Institute of Pathology, Washington, D. C.
Cancer of the prostate is rare in men less than 50 years old, accounting for only 1.1 per cent of all cases of cancer of the prostate.1 However, interest has been directed to this group recently because of the suspicion that the disease has a worse prognosis in younger men. 2- 5 Some urologists are understandably reluctant to perform radical prostatectomy on younger men because of the resultant impotence, sterility and occasional incontinence. We have undertaken this study in order to determine whether the histologic features or the survival statistics differ from those found in older men. MATERIAL AND METHODS
Fifty-one cases of cancer of the prostate in men less than 50 years old were studied. These cases were accessioned in the Prostatic Tumor Registry, sponsored by the American Urological Association at the Armed Forces Institute of Pathology (AFIP) between March 1945 and April 1963. The criteria for selection were 1) a definite histologic diagnosis of cancer of the prostate, made by us, 2) no evidence of another primary tumor and 3) a minimum of 5-year followup. The patients in this study could be divided into 2 groups: 47 patients in whom the diagnosis was made clinically (designated as group A) and 4 patients in whom the diagnosis was made at Accepted for publication January 2, 1969. This investigation was supported in part by the Veterans Administration Cooperative Urological Research Group and by Public Health Service Fellowship Grant 1-F2-CA-34, 856-01 from the National Cancer Institute. 1 Tjaden, H.B., Culp, D. A. and Flocks, R. H.: Clinical adenocarcinoma of the prostate in patients under 50 years of age. J. Urol., 93: 618, 1965. 2 Grabstald, H.: Radical treatment for all but exceptional cases. Issues Curr. Med. Pract., 3: 10, 1966. 3 Lipworth, L.: End results in cancer of the prostate.Nat. Cancer Inst. Monogr., 15: 159, 1964. 4 Rosenberg, S. E.: Is carcinoma of the prostate less serious in older men? J. Amer. Geriat. Soc., 13: 791, 1965. 5 Turner, R. D. and Belt, E.: A study of 229 consecutive cases of total perineal prostatectomy for cancer of the prostate. J. Urol., 77: 62, 1957.
autopsy (designated as group B). In 34 patients of group A the material was sent to us at the time of diagnosis (group Al), and in the remaining 13 patients (group A2) the material was sent to us after the patient had died. The latter group (A2), by necessity, has been excluded from calculation of survival curves, as are the 4 patients whose cancer was found at autopsy (group B). Histologic material available for examination consisted of hematoxylin and eosin-stained sections of tissue obtained by needle biopsy, transurethral resection, prostatectomy or autopsy (in some instances more than one of these). A tumor grade was assigned to each case. Grade 1 indicates tumors that consist of well-differentiated glands lined by epithelium showing minimal anaplasia (fig. 1). At the opposite extreme, grade 3 tumors show little or no glandular differentiation and the epithelial cells display marked anaplasia (fig. 2). Grade 2 indicates intermediate tumors with glands that are irregular and lined by cells showing moderate anaplasia (fig. 3). CLINICAL OBSERVATIONS
The clinical findings are summarized in table 1. The ages ranged from 27 to 49 years with a mean of 44.24 years. There were 35 Caucasians, 11 Negroes and 5 patients in whom race was unspecified. A physician was consulted because of symptoms referable to the prostate in 33 of the 51 cases. In the remaining 18 cases the disease was detected as a result of routine physical examination. The presenting symptoms fell into 2 classes: 1) urinary complaints (hesitancy, frequency, obstmction, nocturia, dysuria, hematuria, etc.) resulting from benign prostatic hypertrophy or early symptomatic carcinomas and 2) pain due to metastasis from more advanced carcinomas. All patients who presented with pain had metastasis at the time of diagnosis. Information concerning the digital examination of the prostate at the time of diagnosis was available on 38 of the 51 patients. In only 2 of these was the prostate considered normal (patients 940888 and 1023229). 726
CANCER OF PROS TA TE IN 1\l!EN LESS 'l'HAN 50 YEARS OLD
FIG. 1. Grade 1 carcinoma of prostate. H & E lOOX (AFIP negatives 68-3564 and 68-3572). Metastatic lesions were noted at diagnosis in 19 cases but only 3 of these were in group Al, the group in which the least bias in selection would be expected. ANALYSIS OF SURVIVAL RATES
Over-all survival. In trying to arrive at a reliable index of the degree of malignancy of these tumors we have calculated the survival rates and compared them to those for a group of patients more than 50 years old with cancer of the prostate. That group consisted of 210 patients selected from the Veterans Administration Cooperative Urological Research Group Study. 6 All patients in this group were more than 50 years old and the mean age for the group was 69 years. The diagnosis of carcinoma of the prostate in these patients was made on histologic examination of the needle biopsy specimens. Followup informa6 Veterans Adminsitration Co-operative Urological Research Group: Carcinoma of the prostate: a continuing co-operative study. J. Urol., 91: 590,
1964.
727
,- FIG. 2. Grade 3 carcinoma of prostate. H & E lOOX (AFIP negatives 68-3562 and 68-3561). tion was available on all patients. These tumors were graded in the same manner as our 51 cases. All survival curves have been calculated by the life-table method.7 The uppermost curve in figure 4 shows the over-all survival of the 34 patients less than 50 years old who were accessioned at the AFIP at the time of diagnosis (group Al). The middle curve represents the group of 210 Veterans Administration (VA) patients more than 50 years old. These curves were constructed from computations based on deaths from all causes and, since death from causes other than cancer of the prostate would be expected to rise with increasing age, one might attribute the difference in the 2 curves to this factor alone. However, if similar curves are plotted for cancer deaths only the differences between them are still quite marked. The 5-year survival rates for cancer deaths only in the 2 groups are 86 per cent for those less than 7 Cutler, S. J.: International symposium on end results of cancer therapy. Computation of survival rates. Nat. Cancer Inst. Monogr., 15: 381, 1964.
728
BYAR AND MOS'.rOFI
Frn. 3. Grade 2 carcinoma of prostate. H & E lOOX (AFIP negatives 68-356,5 and 68-3566).
,50 and 63 per cent for those more than 50. The lowest curve in figure 4 was calculated from data taken from the article by Tjaden and associates.1 Superficially this curve appears quite dissimilar i,o the one for our series. However, only 11 per cent of their cases were picked up on routine physical examination, before the appearance of symptoms, whereas 38 per cent of our cases were found on routine physical examination. The proportion of this 38 per cent, made up of men on active duty in the military services, was much higher than what would be expected from the composition of our whole sample. Since complete physical examination, including rectal palpation, is required annually for men more than 40 years old on active duty, a larger proportion of our cases was diagnosed before the appearance of symptoms and the survival curve reflects the earlier diagnosis by showing a better prognosis. Survival by tumor grade. No firm conclusions can be drawn from the over-all survival figures just discussed because they must necessarily
reflect the composition of the samples studied. However, all tumors in both groups were assigned histologic grades and thus more accurate comparisons can be made when each grade is considered separately. burv1val curves constructed individually for each grade in the 2 groups show that the prognosis is still better for patients less than 50 years old (fig. 5). This graph was constructed using deaths from all causes, but the same result was obtained when deaths from cancer alone were plotted, though the differences were a little less marked. The greatest difference in survival, when all causes of death are taken into account, occurs in the grade 2 tumors. In table 2 the observed cancer deaths per 1,000 patient-months of observation in the 2 age groups are compared by grade. Thus, whether comparisons are based on all causes of death or on cancer deaths alone there are more deaths in the older age group for all 3 tumor grades, but the greatest difference occurs in the grade 2 tumors. The evidence presented here suggests that the prognosis for carcinoma of the prostate in men le8s than ,50 years old is no worse than that found in older men, even when tumor grade is taken into account, and it may be better. The limitation imposed by the small number of patients less than 50 years old available for study precludes a stronger statement. Importance of symptoms at the time of diagnosis. The presence of symptoms at the time of diagnosis is associated with a more advanced tumor grade and thus with a worse prognosis (table 3). ]t is also clear that the 3 groups are not comparable with regard either to presence of symptoms or tumor grade, since those patients in the last 2 groups have a much larger proportion of gra.de 2 and 3 tumors and a larger proportion of them had symptoms at the time of diagnosis. In group Al only 2 of 7 patients with grade 1 tumors had symptoms when first seen, but 17 of 27 patients with grades 2 and 3 tumors presented with symptoms. Grade 1 tumors were much more common among patients who did not have initial symptoms (5 of 15) than among those who did (2 of 19). However, among those patients with no symptoms, 8 were grade 2 and 2 were grade 3. Thus, the absence of symptoms at the time of diagnosis does not exclude the possibility of a grade 2 or 3 tumor. In group A2 all but one tumor was grnde 3 and all patients dierl of cancer of the prostate with
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Fm. 5. Survival curves for cancer of prostate based on all causes of death, by age group and tumor grade. Roman numerals refer to grade of tumor. widespread metastasis. Only 2 of 13 patients had no symptoms when the diagnosis was first made. One was detected on routine physical examination and the other patient was admitted for a bleeding duodenal ulcer. The effect of symptoms at the time of first diagnosis on the survival curves is based on all causes of death in group Al (fig. 6). Clearly the absence of symptomR, even for a grade 2 tumor, is associated with a good prognosis, while the presence of symptoms is ominous. Importance of metastasis at time of diagnosis. No patient in our series with grade 1 tumors had metastatic lesions at the time of diagnosis or, conversely, all patients with metastasis had grade
2 or 3 tumors, mostly grade 3 (table 4). However, the 3 subgroups are not comparable; the patients in the last 2 groups were selected because of death and all but one of them had metastasis at the time of diagnosis. Presence of metastasis at the time of diagnosis in group lA is reflected much more markedly in the survival curves than is the presence of symptoms. At 5 years the 3 patients who had presented with metastasis were dead, but 20 of 31 patients without metastasis were alive (table 1). The mean survival time of those patients who presented with metastasis was 16.7 months, compared to a mean survival time of 47.2 months for all patients in group Al who died. In group A2 all but 1 patient presented
CANCER OF PROSTATE IN MEN LESS THAN
with metastasis or local extension and the mean survival time of this group was only 17 .6 months. Cases diagnosed at autopsy. In 4 of 51 cases there is no evidence in the clinical records that a histologic diagnosis of cancer of the prostate was TABLE
2. Deaths from cancer of prostate per 1,000
patient-months of observation* Tumor Grade
210 Patients
>
50 Yrs.
34 Patients< 50 Yrs.
2.05 (10) 5. 66 (101) 9.53 (99)
0.00 (7) 2.10 (18) 8.83 (9)
*No.patients shown in parentheses.
3. Relation of symptoms at time of diagnosis to tumor grade in 51 cases of prostatic cancer in men less than 50 years old
TABLE
Tumor Grade
Symptoms at Diagnosis
Group
Al (34 patients accessioned at AFIP at time of diagnosis)
Total 3
No Yes
Totals A2 (13 patients diagnosed while living but accessioned at AFIP after au topsy)
No Yes Unknown
Totals
5
8 10
2 7
15 19
7
18
9
34
0 0 0
0 I 0
2
2 10
12
13
0 3
0
0
B (4 patients diagnosed at autopsy)
No Yes
0 0
Totals
0
0
3
50 YEARS OLD
731
made before autopsy (group B). One patient had unexplained headaches and mental confusion, but roentgenograms of the skull were interpreted as normal. Two months later he died of subarachnoid hemorrhage secondary to multiple brain metastasis. Of the remaining 3 patients, 2 had pain caused by metastatic lesions and the third had uremic coma secondary to urinary obstruction. Both patients with pain had multiple skeletal metastases and both died of bronchopneumonia. It is possibly because such tragic cases in relatively young men (their ages were 40, 41, 41 and 47) make such a strong impression on clinicians that some urologists have suggested that carcinoma of the prostate in young men is a more aggressive disease than that found in older men. Treatment. Because of the nature of our study we have been unable to analyze the effects of treatment in a formal manner. However, we can make a few comments that might be useful to those engaged in controlled studies of various treatments. Of the 18 patients in group Al who were living at the end of the study and who had been followed at least 5 years, only 10 had had prostatectomies other than a transurethral resection. Our longest survivor (141 months) was among those who did not have a prostatectomy. Of course no conclusions can be drawn from these facts since therapy was in no way statistically randomized or controlled, but this does show that a long survival with the tumor presumably present in the body is possible, a factor that must
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YEARS AFTER DIAGNOSIS
6. Survival curves for cancer of I?rosta~e in gro_up Al .based on all causes of death, showing prognosis 1f there are symptoms or metastasis at time of diagnosis m men less than 50 years old. Numbers in parentheses indicate number of patients in each group. ~IG:
732
BYAR AND MOSTOFI
4. Relation of melaslasis at time of diagnosis to grade of tumor in 51 cases of prostatic cancer in rnen less than 50 years old
TABLE
Group
J\fetastasis at Diagnosis
Al (34 patients accesE:ioned at AFIP at time of diagnosis)
No Yes
Totals A2 (13 patients diagnosed while living but accessioned at AFIP after autops:y)
No Yes
No Yes
Totals
.,
Total
0
2
31 3
7
18
34
0 0
0
16
0
Totals B (4 patients diagnosed at autopsy)
Grade
0 0
0
0
8
11
12
12
13
0
0 4
3
4
be considered when comparisons of treatments are contemplated. DISCUSSION
Tjaden and associates reported on 56 cases of prostatic carcinoma in men less than 50 years old, but no attempt was made to compare these patients to an older group1 . However, Grabstald commented on their ·work and stated, "The management of prostatic cancer in the patient under age of fifty years may represent a special problem. First, the disease is less frequently seen in these patients .... Second, and more important, the disease appears to be more malignant in this age group." 2 This impression seems to be based on the fact that only 7 of .56 cases described by Tjaden and associates were considered operable by the generally accepted standards.1 Lipworth discussed the Registrar General's Statistical Review for England and Wales, based on data from 1945 through 1949. The authors of this study found that metastasis from prostatic cancer was more common in younger patients and local invasion in older patients, but Lipworth states that a more detailed breakdown of age of patient and stage of tumor would be necessary to confirm these findings. 3 Rosenberg studied .500 consecutive autopsy cases of cancer of the prostate taken from general and cancer hospitals and found that when age was taken into account and the few "serious cases" were excluded, it appeared that
the younger the patient, the more virulent the tumor. 4 In contrast to these findings, ·Whitmore published a table showing the ratio of incidence to age groups. This ratio decreases dramatically with advancing age, indicating that the disease becomes more aggressive in older patients. 8 Also, Halpert and associates studied 412 autopsy cases of cancer of the prostate, classifying the tumors as diffuse or focal. In the younger patients there was a larger proportion of focal carcinomas and the proportion of diffuse carcinomas increased with advancing age. 9 However, they were unable to decide whether the focal carcinomas are precursors of the diffuse carcinomas or whether the 2 types represent different forms of neoplasia with different biologic behaviors. The results of our study seem to indicate that cancer of the prostate in men less than .50 years old is not a more virulent disease than that found in older men and it may possibly be less virulent. \Ve have also demonstrated, by comparing our survival curve to one based on data taken from the article by Tjaden and associates, that the time of diagnosis is an important variable that profoundly affects the over-all survival curve and may lead to different conclusions. Gilbertsen reported that since 1948 annual physical examination, including digital palpation of the prostate gland, has been performed on 5,897 essentially asymptomatic men at the Cancer Detection Center of the University of Minnesota.10 Thus far, 67 prostatic cancers have been detected and this rate is higher than that for any other cancer found at the center. Definitive diagnosis and treatment in these cases were undertaken by the patient's private physician. The relative survirnl rate for a group of 51 patients on whom a 5-year followup study could be made was 98.9 per cent. In our study grading has been useful because it has permitted a more sensitive comparison between our 2 age groups. Similarly, grading would be useful in making more precise com' \Vhitmore, W. F., J-r.: The rationale and results of ablative surgery for prostatic cancer. Cancer, 16: 1119, 1963. 9 Halpert, B., Sheehan, E. E., Schrnalhorst, W, R. and Scott, R., Jr.: Carcinoma of the prostate. A survey of 5,000 autopsies. Cancer, 16: 737, 1963. 10 Gilbertsen, V. A.: Earlier detection of cancer of the prostate gland. J.A.M.A., 192: 910, 19(35.
of treatment,, when combined with such factors as the stage of the tumor, the age of the patient and any other factors that can be shown to affect survival The effectiveness of grading in this study as an indicator of prognosis is demonstrated by the clear separation between the survival curves in figure 5. In fact, none of our grade 1 patients died of cancer of the prostate. The only death in this group (patient 862182) was due to bronchopneumonia unrelated to cancer. As one would predict, metastasis at the time of diagnosis is a grave sign. In the total series of patients less than 50 years old, all who presented with metastasis were dead within 40 months and their mean survival time was much less than that. This unfortunate fact lends further importance to the necessity of making the diagnosis as as possible. CONCLUSIONS
A group of 51 patients less tban 50 years old, with histologically confirmed cancer of the prostate, has been studied 1vith respect io survival and the histology of the tumor. This group has
been comprtred to a group of 210 more than 50 years old who also had cancer. Calculations of over-all survival and survival by tumor grade showed that the prognosis for cimcer of the prostate in men less than ,50 years old 1s no worse than that found in older m.en and is possibly better. Histologic tumor grading was found to be useful in increasing the sensitivity of comparisons between the 2 age groups. Survival figures for the 3 grades were distinctly different and tumor grade showed some correlation with symptoms and metastasis at the time of diagnosis. The presence of either symptoms or metastasis at the time of diagnosis io associated with a more grave prognosis and, of the 2 conditions, metastasis is by far the worse. On the basis of our study, the most promising approach toward inereasing the survival of patients less than .50 years old with cancer of the prostate would be frn early diagnosis. The nnportance of annual physical eluding digital palpation of the prostate emphasized.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright © 1969 by The Williams & Wilkins Co.
CANCER OF THE PROSTATE IN MEN LESS THAN 50 YEARS OLD: AN ANALYSIS OF 51 CASES DAVID P. BYAR
AND
F. K. MOSTOFI
From the Armed Forces Institute of Pathology, Washington, D. C.
Cancer of the prostate is rare in men less than 50 years old, accounting for only 1.1 per cent of all cases of cancer of the prostate.1 However, interest has been directed to this group recently because of the suspicion that the disease has a worse prognosis in younger men. 2- 5 Some urologists are understandably reluctant to perform radical prostatectomy on younger men because of the resultant impotence, sterility and occasional incontinence. We have undertaken this study in order to determine whether the histologic features or the survival statistics differ from those found in older men. MATERIAL AND METHODS
Fifty-one cases of cancer of the prostate in men less than 50 years old were studied. These cases were accessioned in the Prostatic Tumor Registry, sponsored by the American Urological Association at the Armed Forces Institute of Pathology (AFIP) between March 1945 and April 1963. The criteria for selection were 1) a definite histologic diagnosis of cancer of the prostate, made by us, 2) no evidence of another primary tumor and 3) a minimum of 5-year followup. The patients in this study could be divided into 2 groups: 47 patients in whom the diagnosis was made clinically (designated as group A) and 4 patients in whom the diagnosis was made at Accepted for publication January 2, 1969. This investigation was supported in part by the Veterans Administration Cooperative Urological Research Group and by Public Health Service Fellowship Grant 1-F2-CA-34, 856-01 from the National Cancer Institute. 1 Tjaden, H.B., Culp, D. A. and Flocks, R. H.: Clinical adenocarcinoma of the prostate in patients under 50 years of age. J. Urol., 93: 618, 1965. 2 Grabstald, H.: Radical treatment for all but exceptional cases. Issues Curr. Med. Pract., 3: 10, 1966. 3 Lipworth, L.: End results in cancer of the prostate.Nat. Cancer Inst. Monogr., 15: 159, 1964. 4 Rosenberg, S. E.: Is carcinoma of the prostate less serious in older men? J. Amer. Geriat. Soc., 13: 791, 1965. 5 Turner, R. D. and Belt, E.: A study of 229 consecutive cases of total perineal prostatectomy for cancer of the prostate. J. Urol., 77: 62, 1957.
autopsy (designated as group B). In 34 patients of group A the material was sent to us at the time of diagnosis (group Al), and in the remaining 13 patients (group A2) the material was sent to us after the patient had died. The latter group (A2), by necessity, has been excluded from calculation of survival curves, as are the 4 patients whose cancer was found at autopsy (group B). Histologic material available for examination consisted of hematoxylin and eosin-stained sections of tissue obtained by needle biopsy, transurethral resection, prostatectomy or autopsy (in some instances more than one of these). A tumor grade was assigned to each case. Grade 1 indicates tumors that consist of well-differentiated glands lined by epithelium showing minimal anaplasia (fig. 1). At the opposite extreme, grade 3 tumors show little or no glandular differentiation and the epithelial cells display marked anaplasia (fig. 2). Grade 2 indicates intermediate tumors with glands that are irregular and lined by cells showing moderate anaplasia (fig. 3). CLINICAL OBSERVATIONS
The clinical findings are summarized in table 1. The ages ranged from 27 to 49 years with a mean of 44.24 years. There were 35 Caucasians, 11 Negroes and 5 patients in whom race was unspecified. A physician was consulted because of symptoms referable to the prostate in 33 of the 51 cases. In the remaining 18 cases the disease was detected as a result of routine physical examination. The presenting symptoms fell into 2 classes: 1) urinary complaints (hesitancy, frequency, obstmction, nocturia, dysuria, hematuria, etc.) resulting from benign prostatic hypertrophy or early symptomatic carcinomas and 2) pain due to metastasis from more advanced carcinomas. All patients who presented with pain had metastasis at the time of diagnosis. Information concerning the digital examination of the prostate at the time of diagnosis was available on 38 of the 51 patients. In only 2 of these was the prostate considered normal (patients 940888 and 1023229). 726
CANCER OF PROS TA TE IN 1\l!EN LESS 'l'HAN 50 YEARS OLD
FIG. 1. Grade 1 carcinoma of prostate. H & E lOOX (AFIP negatives 68-3564 and 68-3572). Metastatic lesions were noted at diagnosis in 19 cases but only 3 of these were in group Al, the group in which the least bias in selection would be expected. ANALYSIS OF SURVIVAL RATES
Over-all survival. In trying to arrive at a reliable index of the degree of malignancy of these tumors we have calculated the survival rates and compared them to those for a group of patients more than 50 years old with cancer of the prostate. That group consisted of 210 patients selected from the Veterans Administration Cooperative Urological Research Group Study. 6 All patients in this group were more than 50 years old and the mean age for the group was 69 years. The diagnosis of carcinoma of the prostate in these patients was made on histologic examination of the needle biopsy specimens. Followup informa6 Veterans Adminsitration Co-operative Urological Research Group: Carcinoma of the prostate: a continuing co-operative study. J. Urol., 91: 590,
1964.
727
,- FIG. 2. Grade 3 carcinoma of prostate. H & E lOOX (AFIP negatives 68-3562 and 68-3561). tion was available on all patients. These tumors were graded in the same manner as our 51 cases. All survival curves have been calculated by the life-table method.7 The uppermost curve in figure 4 shows the over-all survival of the 34 patients less than 50 years old who were accessioned at the AFIP at the time of diagnosis (group Al). The middle curve represents the group of 210 Veterans Administration (VA) patients more than 50 years old. These curves were constructed from computations based on deaths from all causes and, since death from causes other than cancer of the prostate would be expected to rise with increasing age, one might attribute the difference in the 2 curves to this factor alone. However, if similar curves are plotted for cancer deaths only the differences between them are still quite marked. The 5-year survival rates for cancer deaths only in the 2 groups are 86 per cent for those less than 7 Cutler, S. J.: International symposium on end results of cancer therapy. Computation of survival rates. Nat. Cancer Inst. Monogr., 15: 381, 1964.
728
BYAR AND MOS'.rOFI
Frn. 3. Grade 2 carcinoma of prostate. H & E lOOX (AFIP negatives 68-356,5 and 68-3566).
,50 and 63 per cent for those more than 50. The lowest curve in figure 4 was calculated from data taken from the article by Tjaden and associates.1 Superficially this curve appears quite dissimilar i,o the one for our series. However, only 11 per cent of their cases were picked up on routine physical examination, before the appearance of symptoms, whereas 38 per cent of our cases were found on routine physical examination. The proportion of this 38 per cent, made up of men on active duty in the military services, was much higher than what would be expected from the composition of our whole sample. Since complete physical examination, including rectal palpation, is required annually for men more than 40 years old on active duty, a larger proportion of our cases was diagnosed before the appearance of symptoms and the survival curve reflects the earlier diagnosis by showing a better prognosis. Survival by tumor grade. No firm conclusions can be drawn from the over-all survival figures just discussed because they must necessarily
reflect the composition of the samples studied. However, all tumors in both groups were assigned histologic grades and thus more accurate comparisons can be made when each grade is considered separately. burv1val curves constructed individually for each grade in the 2 groups show that the prognosis is still better for patients less than 50 years old (fig. 5). This graph was constructed using deaths from all causes, but the same result was obtained when deaths from cancer alone were plotted, though the differences were a little less marked. The greatest difference in survival, when all causes of death are taken into account, occurs in the grade 2 tumors. In table 2 the observed cancer deaths per 1,000 patient-months of observation in the 2 age groups are compared by grade. Thus, whether comparisons are based on all causes of death or on cancer deaths alone there are more deaths in the older age group for all 3 tumor grades, but the greatest difference occurs in the grade 2 tumors. The evidence presented here suggests that the prognosis for carcinoma of the prostate in men le8s than ,50 years old is no worse than that found in older men, even when tumor grade is taken into account, and it may be better. The limitation imposed by the small number of patients less than 50 years old available for study precludes a stronger statement. Importance of symptoms at the time of diagnosis. The presence of symptoms at the time of diagnosis is associated with a more advanced tumor grade and thus with a worse prognosis (table 3). ]t is also clear that the 3 groups are not comparable with regard either to presence of symptoms or tumor grade, since those patients in the last 2 groups have a much larger proportion of gra.de 2 and 3 tumors and a larger proportion of them had symptoms at the time of diagnosis. In group Al only 2 of 7 patients with grade 1 tumors had symptoms when first seen, but 17 of 27 patients with grades 2 and 3 tumors presented with symptoms. Grade 1 tumors were much more common among patients who did not have initial symptoms (5 of 15) than among those who did (2 of 19). However, among those patients with no symptoms, 8 were grade 2 and 2 were grade 3. Thus, the absence of symptoms at the time of diagnosis does not exclude the possibility of a grade 2 or 3 tumor. In group A2 all but one tumor was grnde 3 and all patients dierl of cancer of the prostate with
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Y,,s Yes Yes
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C--Cauca.sian, N-~Negroid, G·-ufu:;pec.i.fied. parentlwtica.1 adjective. TUR--1.ransuretbral resection c,f r1rostctt,e. Orch.----orcl1ieutc:1rly prostatectom,y unless modified C herno. ----chemot tern.py. Dead-C--·death from cancer of pro:'::tate. DeacLN-- norH'.:&nccr deaLli, Dead-U-- cause of dc:;:1,tli unknown,
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BYAR AND JVIOSTOFI 100 90
80
~
~
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YEARS AFTER DIAGNOSIS
Fm. 4. Survival curves for cancer of prostate based on all causes of death 1 0 0 - = = - - - - - - - - - - - - - - -..... 90 80
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3
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YEARS AFTER DIAGNOSIS
Fm. 5. Survival curves for cancer of prostate based on all causes of death, by age group and tumor grade. Roman numerals refer to grade of tumor. widespread metastasis. Only 2 of 13 patients had no symptoms when the diagnosis was first made. One was detected on routine physical examination and the other patient was admitted for a bleeding duodenal ulcer. The effect of symptoms at the time of first diagnosis on the survival curves is based on all causes of death in group Al (fig. 6). Clearly the absence of symptomR, even for a grade 2 tumor, is associated with a good prognosis, while the presence of symptoms is ominous. Importance of metastasis at time of diagnosis. No patient in our series with grade 1 tumors had metastatic lesions at the time of diagnosis or, conversely, all patients with metastasis had grade
2 or 3 tumors, mostly grade 3 (table 4). However, the 3 subgroups are not comparable; the patients in the last 2 groups were selected because of death and all but one of them had metastasis at the time of diagnosis. Presence of metastasis at the time of diagnosis in group lA is reflected much more markedly in the survival curves than is the presence of symptoms. At 5 years the 3 patients who had presented with metastasis were dead, but 20 of 31 patients without metastasis were alive (table 1). The mean survival time of those patients who presented with metastasis was 16.7 months, compared to a mean survival time of 47.2 months for all patients in group Al who died. In group A2 all but 1 patient presented
CANCER OF PROSTATE IN MEN LESS THAN
with metastasis or local extension and the mean survival time of this group was only 17 .6 months. Cases diagnosed at autopsy. In 4 of 51 cases there is no evidence in the clinical records that a histologic diagnosis of cancer of the prostate was TABLE
2. Deaths from cancer of prostate per 1,000
patient-months of observation* Tumor Grade
210 Patients
>
50 Yrs.
34 Patients< 50 Yrs.
2.05 (10) 5. 66 (101) 9.53 (99)
0.00 (7) 2.10 (18) 8.83 (9)
*No.patients shown in parentheses.
3. Relation of symptoms at time of diagnosis to tumor grade in 51 cases of prostatic cancer in men less than 50 years old
TABLE
Tumor Grade
Symptoms at Diagnosis
Group
Al (34 patients accessioned at AFIP at time of diagnosis)
Total 3
No Yes
Totals A2 (13 patients diagnosed while living but accessioned at AFIP after au topsy)
No Yes Unknown
Totals
5
8 10
2 7
15 19
7
18
9
34
0 0 0
0 I 0
2
2 10
12
13
0 3
0
0
B (4 patients diagnosed at autopsy)
No Yes
0 0
Totals
0
0
3
50 YEARS OLD
731
made before autopsy (group B). One patient had unexplained headaches and mental confusion, but roentgenograms of the skull were interpreted as normal. Two months later he died of subarachnoid hemorrhage secondary to multiple brain metastasis. Of the remaining 3 patients, 2 had pain caused by metastatic lesions and the third had uremic coma secondary to urinary obstruction. Both patients with pain had multiple skeletal metastases and both died of bronchopneumonia. It is possibly because such tragic cases in relatively young men (their ages were 40, 41, 41 and 47) make such a strong impression on clinicians that some urologists have suggested that carcinoma of the prostate in young men is a more aggressive disease than that found in older men. Treatment. Because of the nature of our study we have been unable to analyze the effects of treatment in a formal manner. However, we can make a few comments that might be useful to those engaged in controlled studies of various treatments. Of the 18 patients in group Al who were living at the end of the study and who had been followed at least 5 years, only 10 had had prostatectomies other than a transurethral resection. Our longest survivor (141 months) was among those who did not have a prostatectomy. Of course no conclusions can be drawn from these facts since therapy was in no way statistically randomized or controlled, but this does show that a long survival with the tumor presumably present in the body is possible, a factor that must
100 , ----·o------~o---°'-..._ No Symptoms (/5)
80
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90
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3;:
50
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30 20 10
' , , No Metastases (31) \
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\
\
\
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·------------..._,
Symptoms (/9) \
\
I
I
\
\
I
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YEARS AFTER DIAGNOSIS
6. Survival curves for cancer of I?rosta~e in gro_up Al .based on all causes of death, showing prognosis 1f there are symptoms or metastasis at time of diagnosis m men less than 50 years old. Numbers in parentheses indicate number of patients in each group. ~IG:
732
BYAR AND MOSTOFI
4. Relation of melaslasis at time of diagnosis to grade of tumor in 51 cases of prostatic cancer in rnen less than 50 years old
TABLE
Group
J\fetastasis at Diagnosis
Al (34 patients accesE:ioned at AFIP at time of diagnosis)
No Yes
Totals A2 (13 patients diagnosed while living but accessioned at AFIP after autops:y)
No Yes
No Yes
Totals
.,
Total
0
2
31 3
7
18
34
0 0
0
16
0
Totals B (4 patients diagnosed at autopsy)
Grade
0 0
0
0
8
11
12
12
13
0
0 4
3
4
be considered when comparisons of treatments are contemplated. DISCUSSION
Tjaden and associates reported on 56 cases of prostatic carcinoma in men less than 50 years old, but no attempt was made to compare these patients to an older group1 . However, Grabstald commented on their ·work and stated, "The management of prostatic cancer in the patient under age of fifty years may represent a special problem. First, the disease is less frequently seen in these patients .... Second, and more important, the disease appears to be more malignant in this age group." 2 This impression seems to be based on the fact that only 7 of .56 cases described by Tjaden and associates were considered operable by the generally accepted standards.1 Lipworth discussed the Registrar General's Statistical Review for England and Wales, based on data from 1945 through 1949. The authors of this study found that metastasis from prostatic cancer was more common in younger patients and local invasion in older patients, but Lipworth states that a more detailed breakdown of age of patient and stage of tumor would be necessary to confirm these findings. 3 Rosenberg studied .500 consecutive autopsy cases of cancer of the prostate taken from general and cancer hospitals and found that when age was taken into account and the few "serious cases" were excluded, it appeared that
the younger the patient, the more virulent the tumor. 4 In contrast to these findings, ·Whitmore published a table showing the ratio of incidence to age groups. This ratio decreases dramatically with advancing age, indicating that the disease becomes more aggressive in older patients. 8 Also, Halpert and associates studied 412 autopsy cases of cancer of the prostate, classifying the tumors as diffuse or focal. In the younger patients there was a larger proportion of focal carcinomas and the proportion of diffuse carcinomas increased with advancing age. 9 However, they were unable to decide whether the focal carcinomas are precursors of the diffuse carcinomas or whether the 2 types represent different forms of neoplasia with different biologic behaviors. The results of our study seem to indicate that cancer of the prostate in men less than .50 years old is not a more virulent disease than that found in older men and it may possibly be less virulent. \Ve have also demonstrated, by comparing our survival curve to one based on data taken from the article by Tjaden and associates, that the time of diagnosis is an important variable that profoundly affects the over-all survival curve and may lead to different conclusions. Gilbertsen reported that since 1948 annual physical examination, including digital palpation of the prostate gland, has been performed on 5,897 essentially asymptomatic men at the Cancer Detection Center of the University of Minnesota.10 Thus far, 67 prostatic cancers have been detected and this rate is higher than that for any other cancer found at the center. Definitive diagnosis and treatment in these cases were undertaken by the patient's private physician. The relative survirnl rate for a group of 51 patients on whom a 5-year followup study could be made was 98.9 per cent. In our study grading has been useful because it has permitted a more sensitive comparison between our 2 age groups. Similarly, grading would be useful in making more precise com' \Vhitmore, W. F., J-r.: The rationale and results of ablative surgery for prostatic cancer. Cancer, 16: 1119, 1963. 9 Halpert, B., Sheehan, E. E., Schrnalhorst, W, R. and Scott, R., Jr.: Carcinoma of the prostate. A survey of 5,000 autopsies. Cancer, 16: 737, 1963. 10 Gilbertsen, V. A.: Earlier detection of cancer of the prostate gland. J.A.M.A., 192: 910, 19(35.
of treatment,, when combined with such factors as the stage of the tumor, the age of the patient and any other factors that can be shown to affect survival The effectiveness of grading in this study as an indicator of prognosis is demonstrated by the clear separation between the survival curves in figure 5. In fact, none of our grade 1 patients died of cancer of the prostate. The only death in this group (patient 862182) was due to bronchopneumonia unrelated to cancer. As one would predict, metastasis at the time of diagnosis is a grave sign. In the total series of patients less than 50 years old, all who presented with metastasis were dead within 40 months and their mean survival time was much less than that. This unfortunate fact lends further importance to the necessity of making the diagnosis as as possible. CONCLUSIONS
A group of 51 patients less tban 50 years old, with histologically confirmed cancer of the prostate, has been studied 1vith respect io survival and the histology of the tumor. This group has
been comprtred to a group of 210 more than 50 years old who also had cancer. Calculations of over-all survival and survival by tumor grade showed that the prognosis for cimcer of the prostate in men less than ,50 years old 1s no worse than that found in older m.en and is possibly better. Histologic tumor grading was found to be useful in increasing the sensitivity of comparisons between the 2 age groups. Survival figures for the 3 grades were distinctly different and tumor grade showed some correlation with symptoms and metastasis at the time of diagnosis. The presence of either symptoms or metastasis at the time of diagnosis io associated with a more grave prognosis and, of the 2 conditions, metastasis is by far the worse. On the basis of our study, the most promising approach toward inereasing the survival of patients less than .50 years old with cancer of the prostate would be frn early diagnosis. The nnportance of annual physical eluding digital palpation of the prostate emphasized.