Carcinoma of the prostate is defined as latent when it is detected at autopsy or in surgical specimens from patients in whom carcinoma was clinically not ...
Prostate
Latent Carcinoma of the Prostate IVAR LIAVAG, THORSTEIN
B. HARBITZ, and OLAV A. HAUGEN
Diakonissehusets Hospital, Department of Surgery and Ulleval Hospital, Department of Pathology, Oslo, Norway
Carcinoma of the prostate is defined as latent when it is detected at autopsy or in surgical specimens from patients in whom carcinoma was clinically not suspected. When symptoms and/or signs have aroused suspicion of prostatic malignancy, the term clinicalfy manifest carcinoma of the prostate is used. Carcinoma of the prostate is now the most frequent form of cancer among Norwegian men, accounting for 19 per cent of all new cases of malignant neoplasms in men in the period 1964-1966 (The Cancer Registry of Norway, 1969). The annual number of new cases of prostatic carcinoma has increased from 708 in 1960 to about 900 in 1970. This increasing number of registered cases is mainly due to an increase in the mean age of the male population during this period (PEDERSEN, 1971). During the last 10 to 15 years, the age-specific incidence rates of prostatic carcinoma in men under 70 years of age have remained nearly constant. After this age, however, there has been a slight increase. There are reasons to believe that this increased incidence can be ascribed to improvement in diagnosis and higher autopsy rates. There is a great discrepancy between the occurrence of latent and clinically manifest carcinoma of the prostate. At autopsy, prostatic carcinoma is frequently found in elderly men, whereas prostatic carcinoma as a cause of death is relatively rare. However, in patients with cliniclily manifest carcinoma of the prostate, there is a high risk of subsequent death from the malignancy: Within a mean of two and a half years after the diagnosis is made, three fourths of the patients are dead (JOHNsON,1962). From the study of latent carcinoma, information can be obtained about the natural history of prostatic carcinoma and the relation between histological pattern and clinical course.
Histological Criteria of Prostatic Carcinoma The generally accepted criteria of malignancy should also be applied in the diagnosis of latent prostatic carcinoma. The evidence of malignancy is based on an evaluation of 1) cellular irregularities, 2) atypical glandular structures and 3) tissue invasion. Absolute criteria of malignancy are 1) invasion of perineural spaces, 2) invasion of blood vessels, 3) local or capsular invasion and 4) periprostatic invasion or distant metastases. In latent carcinoma of the prostate it may be difficult to tell whether true local or capsular invasion is present. When conclusive invasive properties
E. Grundmann et al. (eds.), Current Problems in the Epidemiology of Cancer and Lymphomas © Springer-Verlag Berlin • Heidelberg 1972
1. LIAVAG, T. B. HARBITZ, and O. A. HAUGEN
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can not be recognized, the structures should not be regarded as carcinomas. For these lesions we suggest the term atypical glandular proliferations.
Frequency of Latent Prostatic Carcinoma Several autopsy and biopsy studies of prostatic carcinoma have been carried out in Norway during the last decade (Table 1). In two autopsy series of patients 40 years old or more, latent carcinoma was found in 26.5 and 32.0 per cent, respectively. The age-specific prevalence of latent carcinoma in these studies is similar to that reported from Denmark (STARKLINT, 1950), Great Britain (FRANKS, 1954), U.S.A. (BUTLER, BRAUNSTEIN, FREIMAN and GALL, 1959) and Japan (KARUBE, 1961; OOTA, 1961). On the other hand, the death rates of prostatic carcinoma in Japan differ significantly from those in the aforementioned countries (WYNDER, MABUCHI and WHITMORE, 1971). The frequency of latent carcinoma is substantially higher in autopsy than in biopsy series (Table 1). In three Norwegian series of patients treated for urinary obstruction, the percentage of latent carcinoma (stage I) varied from 1.2 to 4.8 (Table 1). The lower frequency of latent carcinoma in biopsy material is mainly due to the fact that transurethral or open prostatectomy leaves the peripheral parts of the gland behind in which carcinoma is likely to occur. Table 1. Frequency of latent prostatic carcinoma in autopsy and biopsy series of Norwegian men Authors
Material
No. of cases
No. with carcinoma
%
LIAVAG (1967) HARBITZ and HAUGEN (1971 a) JOHNSON (1962) ANDERSEN (1959, 1971) MILLER and SELJELID (1971)
Autopsy Autopsy Biopsy Biopsy Biopsy
340 206 1434 6189 566
90 66 17 142 27
26.5 32.0 1.2 2.3 4.8
Table 2. Occurrence of prostatic carcinoma in Norwegian men operated on for urinary obstruction Authors
No. of cases
Prostatic carcinoma
%
Latent carcinoma a
JOHNSON (1962) ANDERSEN (1959, 1971) MILLER and SELJELID (1971)
1434 6189 3636
139 796 427
9.7 12.9 11.7
12.2 17.8 30.0
a In
% of all prostatic carcinomas.
In biopsy series, the occurrence of latent carcinomas as percentage of all prostatic carcinomas ranged from 12.2 to 30 per cent (Table 2). BO]SEN (1961) found that the percentage reported in the literature showed a similar variation, though in most series latent carcinoma accounted for about 10 per cent of all prostatic carcinomas. The variation in the reported frequency of latent carcinoma in biopsy series is probably mostly due to differences in the diagnostic ability of the surgeons and different histological criteria of cancer.
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In an autopsy study (HARBITZ and HAUGEN, 1971 a), atypical glandular proliferations were found in 10 per cent of the prostates studied. MILLER and SELJELID (1971) observed marked or slight atypical glandular proliferation in 8.1 per cent of cases operated on for urinary obstruction. Of 100 cases (2.8 per cent) with marked atypia which were followed for 7 years after the operation, 4 died from prostatic carcinoma within 5 years. The significance of these atypical structures is not clear, but they might represent premalignant lesions.
Relationship between Prostatic Carcinoma and Age The frequency of latent carcinoma found at autopsy increases with age, approaching 50 per cent in patients 80 years old or more (Table 3). The age-specific incidence rates of all prostatic carcinomas also increase steadily with age (The Cancer Registry of Norway, 1969). Table 3. Occurrence of latent prostatic carcinoma by age in an autopsy series (LIAVAG, 1967) No. with carcinoma
%
Age
No. of autopsies
40--49 50-59 60-69 70-79 80-89 90-99
25 54 122 91 45 3
28 26 21 2
8.0 20.0 23.0 28.6 46.7 66.7
Total
340
90
26.5
2 11
In an autopsy study, LIAVAG (1967) found that the weight of prostates with latent carcinoma or benign hyperplasia increased steadily with age. After the age of 60, prostates with latent carcinoma weighed significantly more than those showing benign hyperplasia only (Fig. 1). The weight of the latent carcinoma itself also 80 g
60
- - Carcinoma •••••• _. Hyperplasia Without carcinoma or hyperplasia
40 20
o Age
Fig. 1. Mean weight of prostates without carcinoma or hyperplasia, with benign hyperplasia, or with latent carcinoma in relation to age of the patients (LIAVAG, 1967)
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1. LIAVAG, T. B.
HARBITZ,
and
o. A. HAUGEN
increased with age to a peak in the eighth decade (Fig. 2). Furthermore, the frequency of cellular atypia and undifferentiated growth in glands with latent carcinoma increased with age (Table 4). These findings are supported by other autopsy studies (STARKLINT, 1950; LUNDBERG and BERGE, 1970). Hence, large tumours are associated with marked cellular atypia and a high frequency of undifferentiated growth. These observations are probably of importance in the treatment of patients with carcinoma of the prostate. 0.20 g
0.15 0.10 0.05 040 Age
Fig. 2. Mean weights of 83 latent carcinomas in relation to age of the patients
(LIAVAG,
1967)
Table 4. Frequency of undifferentiated growth in latent prostatic carcinoma by age (LIAVAG, 1967) No. of prostates
Age
With carcinoma
With undiff. growth
% 0.0 18.2 28.6 50.0 43.5 36.7
40-49 50-59 60-69 70-79 80+
28 26 23
0 2 8 13 10
Total
90
33
2 11
Etiology and Pathogenesis The etiology of carcinoma of the prostate is unknown, and several pathogenetic factors are probably involved. There is strong evidence in support of a causal relationship between local atrophy and the development of prostatic carcinoma (for ref. see LIAVAG, 1968). The local atrophy frequently seen with advancing age may be induced by inflammation, nutritional deficiencies and local ischemia. However, in an autopsy study, marked prostatitis was not more frequent in glands with latent carcinoma than in noncarcinomatous glands (LIAVAG, 1967). In a study on blood flow of the prostate
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measured by means of the hydrogen polarography method, there was no significant difference in mean flow in glands with carcinoma and benign hyperplasia (HAFFNER and LIAVAG, 1969). Based on clinical observations (HUGGINS, STEVENS and HODGES, 1941), morphological studies of endocrine organs (SOMMERS, 1957) and biochemical analyses of human plasma and urine (BULBROOK, FRANKS and GREENWOOD, 1959; STERN, HOPKINS, WEINER and MARMORSTON, 1964) the concept of some form of endocrine imbalance in patients with prostatic carcinoma has gained wide acceptance. However, further studies in man are needed to evaluate the role of certain endocrine glands for the development of prostatic malignancy. In an autopsy series of Norwegian men, studies of the pituitary gland, the adrenal glands, the testicles and the prostate are in progress (HARBITZ and HAUGEN, 1971 b). The preliminary results indicate further evidence for structural differences in the endocrine glands of men with benign nodular hyperplasia or latent carcinoma of the prostate. Before the age of 70 years, men with latent prostatic carcinoma had significantly lower mean testicular weights than patients with benign nodular hyperplasia. On the other hand, the latter showed a significant decrease of mean testicular weights with age, whereas no such decrease was found in patients with latent carcinoma of the prostate. The mean pituitary weights were about the same in latent carcinoma and in benign hyperplasia. Patients with latent carcinoma showed a higher frequency of small pituitary adenomata. The mean adrenal weight in patients with latent carcinoma which was not accompanied by benign hyperplasia was significantly higher than in patients with prostates showing benign hyperplasia only. The incidence of prostatic carcinoma is higher in Western than in Eastern Europe, in U.S. Negroes compared with African Negroes, and in Japanese immigrants to the United States compared with native Japanese (WYNDER, MABUCHI and WHITMORE, 1971). This strongly suggests that environmental factors playa role in the pathogenesis of prostatic carcinoma. It has recently been shown in rats and men that there is a selective uptake of androgen by the prostate. Further, the demonstration of androphilic macromolecules in prostatic tissue indicates the presence of specific androgenic receptors in the prostate (TVETER, 1970; TVETER, UNHJEM, ATTRAMADAL, AAKVAAG and HANSSON, 1970). It has already been shown that certain compounds inhibit the action of testosterone by competing for androgenic receptors in the prostate (TVETER, 1970 for ref.). It is therefore possible that certain environmental factors might inhibit or enhance the action of testosterone in the prostate.
Histological Relationship between Latent and Manifest Prostatic Carcinoma In a previous study by STARKLINT (1950), no histological differences between latent and manifest carcinoma of the prostate could be demonstrated. In our studies, the same histological types were observed both in latent and in clinically manifest prostatic carcinomas. However, the frequency of undifferentiated tumours were higher, and cellular atypia more marked in manifest than in latent carcinomas. Dedifferentiation was found to increase with the size of the tumour. Latent carcinomas were usually small, whereas the manifest carcinomas were large, commonly involv-
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I. LIAVAG, T. B. HARBITZ, and O. A. HAUGEN
ing the whole prostate. Thus, the structures of latent and manifest prostatic carcinomas were essentially the same, but differences in size, differentiation and cellular atypia were present.
Biological Relationship between Latent and Manifest Prostatic Carcinoma The question whether latent prostatic carcinoma may develop into clinically manifest carcinoma is of great interest. In an autopsy study (LIAVAG, 1967) of patients previously subjected to prostatic surgery for urinary obstruction, latent prostatic carcinoma had been diagnosed in 3 patients at the time of operation. Within a course of 5 to 18 years they all died with manifest carcinoma of the prostate. The clinical course or latent prostatic carcinoma was studied in two series by BAUER, MCGAVRAN and CARLIN (1960) and MILLER and SELJELID (1971). Within 13 and 7 years, respectively, after the diagnosis was made, about 30 per cent of the patients were dead from prostatic carcinoma. Small and well differentiated lesions had a more favourable prognosis than large and poorly differentiated tumours. It seems justified to conclude that latent carcinomas have the histological characteristics and biological properties of manifest carcinomas. However, the majority of latent carcinomas are small, well differentiated and slowly growing tumours in old men, and no further treatment is required. Prostatic cancer in advanced stages is only amenable to palliative treatment. Our aim should therefore be to diagnose these tumours in an early stage before they have progressed beyond the scope of radical cure. When the age of the patient and the histological pattern of the tumour indicate an unfavourable prognosis, radical treatment is only possible when the cancer remains within the confines of the prostate. On the other hand, when manifestations of the carcinoma are unlikely to appear, a wait and see attitude should be adopted.
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KARUBE, K.: Study of latent carcinoma of the prostate in the Japanese based on necropsy material. Tohoku J. expo Med. 74, 265-285 (1961). LIAVAG, I.: Carcinoma of the prostate. Oslo: Universitetsforlaget 1967, pp. 151. LIAVAG, I.: Atrophy and regeneration in the pathogenesis of prostatic carcinoma. Acta path. microbioI. scand. 73, 338 -350 (1968). LUNDBERG, S., BERGE, T.: Prostatic carcinoma. An autopsy study. Scand. J. Urol. Nephrol. 4,
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MILLER, A., SELJELID, R.: Cellular atypia in the prostate. Scand. J. Urol. Nephrol. 5,17-21 (1971). OOTA, K.: Latent carcinoma of the prostate among the Japanese. Acta. Un. into Cancer 17, 952-957
(1961). PEDERSEN, E.: Personal communication, 1971. SOMMERS, S. c.: Endocrine changes with prostatic carcinoma. Cancer 10, 345-358 (1957). STARKLINT, H.: Undersogelser over latent og manifest prostatacancer. Kobenhavn: Munksgaard 1950, pp. 130. STERN, E., HOPKINS, C. E., WEINER, J. M., MARMORSTON, J.: Hormone excretion patterns in breast and prostate cancer are abnormal. Science 145, 716-719 (1964). The Cancer Registry of Norway: Cancer registration in Norway. The incidence of cancer in Norway 1964--1966. Oslo 1969. TVETER, K. J.: Studies on selective uptake and metabolism of testosterone-3H in the prostate and the seminal vesicles of the rat. Oslo: Universitetsforlaget 1970. TVETER, K. J., UNHJEM, 0., ATTRAMADAL, A., AAKVAAG, A., HANSSON, V.: Androgenic receptors in rat and human prostate. Adv. Biosci. 7, 193-207 (1970). WYNDER, E. L., MABUCHI, K., WHITMORE, W. F., Jr.: Epidemiology of cancer of the prostate. Cancer 28, 344-360 (1971).