- Email: [email protected]
Carcinoma of the Prostate Gland: A Pathologic Study1
CARCINOMA OF THE PROSTATE GLAND: A PATHOLOGIC STUDY1 JAMES E. KAHLER The Mayo Foundation, Rochester, Minnesota
The morbid anatomist, finding an increasingly higher incidence of clinically undiagnosed tumors of a given organ, is apt to remind the clinician of the need for more accurate study of individual cases. He cannot more than postulate what might have happened had the absence of a lethal lesion permitted the continued growth of the early neoplasm he has discovered. The increasing life expectancy of the human race may eventually raise these early tumors from the realm of purely academic to one of vital economic interest, just as increased curiosity has apparently changed the lesion of prostatic carcinoma from one of uncommon occurrence to one of alarmingly increased incidence in the glands of individuals past middle life. Prostatic carcinoma excites interest clinically, surgically and pathologically because of certain conceptions which have arisen concerning it; namely, that its predominant origin is in the posterior lobe of the gland, that its characteristic color grossly is yellow, that it is closely associated with nodular hyperplasia and atrophy, and that it has a tendency to extend beyond the gland early in its course. These conceptions will be discussed in light of results based on a study of 195 cases of carcinoma of the prostate gland. Materials and methods. The material for this study was comprised of: (1) 141 cases in which a d1agnosis of primary carcinoma of the prostate gland was made in the Section on Pathologic Anatomy at the clinic and (2) fifty-four cases of prostatic carcinoma which were found on examining additional sections of 490 prostate glands, unselected except that the gland had been diagnosed nonmalignant both clinically and on routine macroscopic and microscopic postmortem examination. (The routine postmortem microscopic examination consisted of the study of a single section prepared from a block of tissue approximately 1.5 cm. square taken at random from the gland.) Each gland was accurately measured, its weight calculated and its 1 Abstract of thesis submitted to the faculty of the Graduate School of the University of Minnesota in partial fulfillment of the requirements for the degree of Master of Science in Pathology. 557
558
JAMES E. KAHLER
size classified by the method of Teem. It was opened anteriorly through the urethra and fixed in Kaiserling's solution for a minimum of 4 days. The gland was then sectioned perpendicularly to the floor of the urethra at intervals of 4 mm. Any section grossly suspected of cancer was removed for microscopic study. In the case of glands in which carcinoma could not be detected grossly, a transverse section was selected which would cop.tain tissue from the anterior, lateral and posterior lobes. This section was taken in most instances at or just anterior to the verumontanum. If the median lobe was markedly enlarged, in addition to the routine transverse section, a section was taken through this lobe in the long axis of the urethra. Blocks were embedded in paraffin, cut at 8 microns thickness, and the sections were stained with hematoxylin and eosin. The various lobes of the prostate gland were not found to be demarcated from each other by septa of any kind (Johnson, Van Duzen). For purposes of locating small tumors confined to one lobe, the following landmarks were utilized: the posterior lobe was considered to be that portion of the gland lying posterior to a plane passing through the ejaculatory ducts. If these ducts were not included in the section, which in this case would be anterior to the verumontanum, then everything behind a plane passing through the floor of the urethra was considered to be the posterior lobe. The anterior lobe consisted of the tissue forming the roof of the urethra. The lateral lobes consisted of all tissue lying between the anterior and posterior lobes except the narrow strip of glandular tissue forming the floor of the urethra between the internal sphincter and the verumontanum and known as the median lobe. In some cases large "adenomas" of the lateral lobe compressed the posterior lobe and displaced its tissue so that the tissue of the lateral lobe lay posterior to the floor of the urethra as well as laterally. The posterior lobe was then considered to be bounded anteriorly by a line drawn from the midpoint of the floor of the urethra to the prostatic capsule, and touching tangentially the lower edge of the "adenoma." Figure 1 illustrates this plan of subdividing the transverse sections into lobes. The carcinomas forming the basis of this study may be divided into 5 groups: (1) "clinical carcinomas" or those in cases in which a diagnosis of primary prostatic carcinoma was made before the death of the patient; (2) "routine necropsy carcinomas," or those in cases in which the diagnosis of malignancy was made either grossly during routine postmortem examination or microscopically on examination of the single routine
CARCINOMA OF PROSTATE GLAND
559
microscopic section; (3) "hidden carcinomas," or those not diagnosed clinically or at routine postmortem gross or microscopic examination which were discovered by additional sections prepared for use in this study; (4) "unlocalized carcinomas," or those in groups 1, 2, and 3 in cases in which the neoplasm was too large to be contained within a single lobe of the gland, and (5) "localized carcinomas," or those which, by reason of their size, were definitely restricted to a single lobe of the gland and showed no tendency to infiltrate the remaining lobes and which might therefore be considered as having arisen in the particular lobe in which they were found. lobe~
Post. to verurnontanum
Ant. to ve-rumontanum
Urethra
Pre.seuce of marked nodular hyper>r1o.sio. FIG. 1. Boundaries of prostatic lobes in cross section of gland
Results. Of the 195 prostatic carcinomas in this study, 72 were diagnosed clinically and confirmed at postmortem examination, 69 were diagnosed at necropsy alone, and the remaining 54 were discovered as the result of additional sections of 490 prostate glands previously diagnosed as benign both clinically and pathologically. The 436 glands remaining in this last-named group provided an adequate control series for each decade. In the 72 cases in which prostatic carcinoma was diagnosed clinically, the primary diagnosis was made by palpation alone in 23 cases, was supported by biopsy in 30 additional cases, and in 19 cases was aided by the demonstration of distant metastasis. In only 4 of the cases was a small tumor described clinically; 3 of these tumors proved microscopically to involve the entire prostate gland; the fourth was described as a hard
560
JAMES E. KAHLER
nodule in the left lateral lobe. When the patient came to necropsy, no such nodule could be found grossly; but, microscopically, a small carcinoma about 1 cm. in diameter was found in the left lateral lobe just anterior to the posterior lobe in an area of nodular hyperplasia. All of these carcinomas which were diagnosed clinically with the exception of the one just mentioned were recognized on gross postmortem examination. Twenty-five of them (35 per cent) were described as having a yellowish color; the remainder were described as being white, pink, or grayish-white. At the time of postmortem examination, 30 of the 69 tumors (43 per cent) which had not been diagnosed clinically were grossly suspected of being cancer, 12 because of their yellowish color, 6 because of a white or grayish-white granular mass of increased consistency, 2 because of their hemorrhagic appearance, and 8 because of an increased consistency without any color differentiation from the remainder of the gland. In the remaining 2 cases, small firm yellow areas were found in glands which microscopically proved to be carcinomatous throughout. In 3 additional cases, small yellow areas were described as being suspicious of carcinoma but, microscopically, carcinoma was found elsewhere in the gland. In 39 cases, therefore, the postmortem diagnosis of carcinoma depended entirely on the microscopic findings. Re-examination of the glands permitted a gross diagnosis of carcinoma in only 9 cases, whereas, in 7 others, areas suspected of being cancer because of a yellowish color proved not to be the site of the microscopic carcinoma. All of the 54 tumors found by means of additional sections were sufficiently small to be limited definitely to one lobe of the prostate gland. The largest of these tumors was one occupying approximately half of the posterior lobe, being situated on both sides of the midline and measuring 2 cm. in its greatest diameter. On re-examination of this specimen, the bulk of the tumor was found to be sufficiently far from the capsule to make its recognition by rectal palpation improbable. The peak incidence of carcinoma in both the clinical and routine postmortem groups occurred in the eighth decade, whereas that of the carcinomas diagnosed only when additional sections were made occurred in the seventh decade. The average age at which prostatic carcinoma is recognized clinically is given by various authors as 65 years (Barringer, Bumpus, Caulk and Boon-Itt). The average age for the clinical group in this study was 68.4 years, and that for the routine postmortem group was 68.2 years, thereby reducing this apparent difference considerably.
CARCINOMA OF PROSTATE GLAND
561
So few carcinomas in this series occurred before the age of 50 years that for purposes of calculating the general incidence in the series, only the cases of men 50 years of age or older will be considered. In the period from January 1, 1923 to January 1, 1936, carcinoma of the prostate gland was diagnosed at postmortem examination in 110 cases, or a general postmortem incidence in males 50 years of age or more of 4 per cent. Of the 490 specimens of prostate glands of which additional sections were made, 381 were from men 50 years of age or older and, in these, 53 additional carcinomas were found (13.9 per cent). The expected incidence therefore in a general series in which, as here, entire cross sections of the prostate gland are studied, would be 4 per cent plus 13.3 per cent (13.9 per cent of 96 per cent) or 17.3 per cent in men 50 years of age or older. In necropsies of men more than 50 years of age, Rich, employing a single microscopic section, found 14 per cent carcinomas in 292 consecutive postmortem examinations. (From the illustrations in his article it would appear that some of these sections at least represented a considerable portion of an entire cross section through the posterior lobe and adjacent lateral lobes.) Moore reported 21 per cent carcinomas in a series of 229 men over fifty; he employed step block sections at intervals of 4 mm. It is apparent, therefore, that the number of carcinomas found, particularly in the higher age groups, increases in direct proportion to the number of microscopic sections made in the individual cases. Neller and Neuburger found 25 per cent malignant degeneration in men more than sixty years of age. Moore has also found the same increased percentage of carcinoma with advancing age. In 3 of the cases in which prostatic carcinoma was diagnosed clinically and in 39 of those in which it was discovered first at necropsy, the tumor was small enough to be restricted to 1 lobe of the gland. All of the additional 54 carcinomas found on examining additional sections of tissue were localized in one lobe (table 1). It is apparent from table 1 that less than half of the carcinomas arose in the posterior lobe, a finding which is contrary to that of most authors. It must be admitted, however, that because the amount of technical work was prohibitive, no attempt was made by serially sectioning the remainder of the glands containing these carcinomas to prove that the carcinoma remained localized in the lobe of origin. It is reasonable to assume that serial sections would reveal little or no variation from the present results, particularly in view of the work of Moore which indicates that the general
562
JAMES E. KAHLER
progression of primary prostatic cancer is toward the posterior lobe from the other lobes rather than conversely. As has been emphasized before, in most instances gross inspection is of no assistance in localizing a tumor or in determining its size. No carcinoma was found to have its origin in the median lobe, a result which may be partly explained by the method of taking sections. Carcinoma arising in this lobe is exceedingly rare. Bothe reported 1 case in which cancer arose in the subcervical glands, and Ferguson described 24 instances in a series of 205 cases of prostatic carcinoma in which the tumor involved principally the lobules about the neck of the bladder. None of these tumors, however, was definitely stated to have arisen in the median lobe. Caulk and Boon-Itt demonstrated malignancy in tissue removed by transurethral prostatic resection but gave no further TABLE
1.-Lobe of origin of ninety-six localized carcinomas of the prostate gland LOBE
DIAGNOSED
Anterior
... Clinically .... On routine postmortem examination ........ . . . ...... ...... On re-examination.
Total ..
. . . . . . ..
.
. . . . . . .
.....
Lateral
Posterior
I
Median
2
0
17 28
18 24
0 0
46 (48%)
44 (46%)
0
0
1
4 2 6 (6%)
I
pathologic proof that the carcinoma in any of their cases arose in the glands surrounding the vesical neck. The distribution of the localized tumors in the other lobes would seem to be roughly proportional to the area of these lobes as represented in a cross section of the gland. Eight of these 96 localized tumors appeared to be multicentric in origin. In 5 of them the several malignant foci were all within the posterior lobe; in the remaining 3, the foci were in the lateral lobe, either in normal tissue (in two cases) or in an area of nodular hyperplasia (one case). Only 53 per cent of the entire group of 195 carcinomas were recognized grossly at necropsy. After making a microscopic diagnosis of carcinoma in glands which originally appeared grossly benign a macroscopic reexamination of that portion of the gland known to contain carcinoma revealed the gross lesion at this second inspection in only an additional 7 per cent of cases. Failure to recognize these tumors grossly is therefore due to the absence of characteristics sufficiently distinct to differentiate
CARCINOMA OF PROSTATE GLAND
563
them from normal or hypertrophied prostatic tissue. In general, the characteristics of prostatic carcinoma which permit of its recognition grossly are: its consistency, color and the character of its cut surface. Fifty-one per cent of the tumors were recognized because of increased consistency alone; the remainder were recognized because of a yellowish, white, or hemorrhagic tint, with or without an increase in consistency, or in a few instances because the homogeneous surface of the area contrasted with the porous, oozing surface of the surrounding hypertrophic tissue. None of these characteristics, however, either singly or in combination, are pathognomonic of cancer; increased consistency within the prostate gland was seen also in leiomyoma (two instances) in areas of fibrosis representing, usually, healed infarcts or areas of focal atrophy (seven and five instances, respectively), and in chronic hyperplastic inflammatory processes (seventeen instances). A yellow color has long been considered characteristic of prostatic carcinoma, yet only 21 per cent of the tumors in this series had a yellowish tint. In more than half of these cases, the tissue was homogeneously yellow; in the remainder, yellow streaks were separated by white or semitranslucent bands. A yellowish tint, however, is also seen in tuberculosis and in both acute and chronic pyogenic inflammation of the prostate gland. In 16 cases a localized yellowish area of increased consistency was described grossly for which no microscopic explanation could be found and the carcinoma was discovered in a distant part of the gland where it was not previously suspected. In an additional 6 cases, small yellow areas of increased consistency were seen grossly in glands which microscopically proved to be neoplastic throughout. Sudan III stains on frozen sections indicate that the yellowish tint of prostatic carcinoma is not entirely dependent on the fat content and may therefore be associated with some form of urochrome pigment so prevalent in the urinary tract. Carcinomas of the prostate gland which appear white are most frequently confused with areas of fibrosis or old healed infarcts. The presence of hemorrhage within the tumor is quite misleading and may be simulated by fresh hemorrhagic infarcts. In this connection it is interesting to note that of the control group of 436 cases in which no carcinoma was found, in 62 cases the glands were suspected of containing small early carcinomas because of their gross appearance; microscopically, however, these areas proved to be ones of atrophy, leiomyoma, hyaline fibrosis, inflammation, infarction, and so forth. The suggested classifications of prostatic carcinomas are at present
564
JAMES E. KAHLER
both numerous and confusing. The tumors under consideration were therefore divided into only 2 groups, that is, squamous-cell carcinomas and adenocarcinomas, each group being subdivided according to the grade of malignancy (according to the method of Broders). In this way as satisfactory a mental picture of the microscopic appearance of an individual tumor can be conveyed as by lengthy descriptions. Of the total of 195 tumors, only 6 (3 per cent), were of the squamouscell variety, the remainder being adenocarcinomas. Four of the squamous-cell carcinomas were of grade 2 (on a basis of 1 to 4) ; the remaining 2 were of grade 3. The grade of malignancy of the adenocarcinomas was as follows: grade 1, 19 per cent; grade 2, 50 per cent; grade 3, 27.5 per cent, and grade 4, 3.5 per cent. The incidence of grades 1 and 2 malignancy is greater in localized tumors and in the lower age groups. This suggests that tumors of the lower grades of malignancy tend to remain localized longer than the more malignant ones do. In view of the generally accepted fact that the grade of malignancy of a tumor does not ordinarily change over a period of time, it cannot be concluded that small tumors necessarily grow into unlocalized ones (as there are more unlocalized tumors in the higher grades of malignancy). Similarly, size is not a criterion of the age of a tumor. The microscopic diagnosis of prostatic carcinoma, as for other tissues of the body, depends (among other things) on such criteria as undifferentiation of cells, loss of polarity, and invasiveness and avidity for basic dyes. There is, however, one criterion, which may be peculiar to the prostate gland, that supersedes all others: perineural lymphatic involvement. While extension of a carcinoma to a perineural lymphatic lying in its path is not by any means restricted to prostatic carcinoma, the abundance of sympathetic fibers within and particularly around the prostate gland and the apparently ideal conditions for growth of prostatic carcinomas in the lymphatics surrounding these fibers forms a definite basis for its malignancy. The absence of these lymphatic vessels in some areas of carcinoma is outweighed by the fact of the uniformity of their involvement in the case of tumors of questionable or of a low grade of malignancy. It is particularly in the former group, to which the pathologist alludes as "questionable beginning carcinomas," that the finding of perineural lymphatic involvement is of exceptional value. These cases include those in which the acini are small and lined by low columnar cells with deeply staining nuclei suggestive of senile change, and those in which the acini are larger than normal and the cells definitely
565
CARCINOMA OF PROSTATE GLAND
hyperplastic but in which there is insufficient change to make the diagnosis of neoplasia. Extension to the perineural lymphatics was found in the same lowpower microscopic field as the tumor in 100 per cent of the cases of grades 3 and 4 tumors, in 85 per cent of those of grade 2 tumors, and in 87 per cent of those of grade 1 tumors, or a total involvement of 91 per cent (table 2). In two cases of grade 2 tumors, metastasis was found at a distance of nearly 1 cm. from the tumor. Because of the high incidence of involvement, it is logical to assume that additional sections from the same block of tissue would reveal the extension in a percentage approximately 100 (figs. 2 and 3). TABLE
2.-Perineural lymphatic involvement in adenocarcinoma of the prostate gland
GRADE OF MALIGNANCY
TOTAL NUMBER OF CASES
TUMOR
, I 1
CASES IN WHICH PERINEURAL LYMPHATICS 1NERE INVOLVED ------
---.
per cent
Unlocalized Localized
i
I
3 12
- - ----i--U-n-lo-c-al-iz_e_d_ _ l _ _ _ 33 2 Localized ! 27
TOTAL CASES OF INVOLVEMENT - - - -
per cent
66
87
91 97 70
85
--------1-------- -------- ------·-1---------
3
Unlocalized Localized
34 9
100 100
100
-------1--------1---------------
4
Unlocalized Localized
4
2
-~~~
__I_--=
The localized tumors, many of which were small enough to occupy only 1 or 2 low-power microscopic fields, showed as high an incidence of perineural lymphatic involvement as large tumors involving the entire prostate gland. It is evident, therefore, that local removal of the tumor itself, either by transurethral resection or suprapubic prostatectomy, does not eradicate all of the tumor tissue even in the case of neoplasms of a low grade of malignancy. The demonstration of lymphatic pathways direct to bone rather than to the regional nodes (Warren, Harris and Graves) raises the question as to whether an operative procedure could be made sufficiently extensive to hope to cure the disease. Perineural lymphatic involvement was observed in only 50 per cent of the six squamous-cell carcinomas. This apparent difference between the proportion of adenocarcinomas and squamous-cell carcinomas extending to the perineural lymphatics may be due to a difference in properties
566
JAMES E. KAHLER
FIG. 2 upper. Showing perineural lymphatic involvement in an adenocarcinoma of grade 1 (X85), and lower, showing perineural lymphatic involvement in an adenocarcinoma of grade 2 (X85).
of growth or may result from the smallness of the group of squamouscell tumors observed. Fifty-four (51 per cent) of the tumors recognized clinically or grossly
CARCINOMA OF PROSTATE GLAND
567
FIG. 3 upper. Showing perineural lymphatic involvement in an adenocarcinoma of grade 3 (X48), and lower, showing perineural lymphatic involvement in an adenocarcinoma of grade 4 (X85).
at necropsy had metastasized at the time of the patient's death. In the remaining cases, no unexplained metastasis was found when the prostate gland was not grossly malignant. The most common site of metas-
568
JAMES E. KAHLER
tasis was in the lymph nodes, followed in order by metastasis to the lung, pelvic peritoneum and bone. Microscopic study was not made of bones which were not grossly involved, which accounts for the failure to confirm the work of Warren, Harris and Graves on the extension to bone by way of the perineural lymphatics. Direct extension of the prostatic carcinoma occurred first to the bladder, and then to the ureters, seminal vesicles and rectum, in the order given. It would be expected that tumors small enough to be restricted to one lobe of the gland would exhibit less tendency to metastasize than unlocalized tumors; nevertheless, they too showed a definitely increased incidence of metastasis as the grade of malignancy increased. In the cases of unlocalized tumors, distant metastasis was found in 33 per cent of those of grade 1, in 50 per cent of those of grade 2, in 84 per cent of those of grade 3, and in 100 per cent of those of grade 4. When the carcinomatous prostate glands were divided into localized and unlocalized groups and when each was further subdivided into six subgroups (atrophic, normal and hypertrophic, grades 1 to 4), the number of cancers in each group showing distant metastasis was roughly the same. Thus the probability of metastasis from either large or small lesions bears no relationship to the gross size of the prostate gland. Both atrophy (Rich) and adenomatous hyperplasia have been described as precursors of prostatic carcinoma. While it is impossible to prove that either of these do not represent precancerous lesions, it can be shown that this supposition is illogical. Atrophy within the prostate may be seen in 3 general forms: diffuse senile atrophy, focal areas of atrophy, and atrophy produced by compression of nodular hyperplasia. Atrophy was found in 53.3 per cent of the glands containing small carcinomas and in 53.6 per cent of those in the control group. In studying the individual small tumors, 39.6 per cent arose in normal tissue and 43. 7 per cent in atrophic areas. These figures would indicate that the association of atrophy and carcinoma is an incidental one rather than a causal relationship. Similarly the incidence of nodular hyperplasia in the cancer group was 67 per cent and in the control group 64 per cent. Only 16.6 per cent of the localized tumors were found to arise within areas of nodular hyperplasia. Perhaps of greater significance is the fact that, in this series of cases, no transition could be found between the cancer and the benign hyperplasia surrounding it. In all of the cases in which the carcinoma occu-
CARCINOMA OF PROSTATE GLAND
569
pied a part of the area of nodular hyperplasia, the differences between the 2 types of tissue in the same microscopic field were sharp and distinct. In several cases in which cancer was found at necropsy, tissue removed by transurethral resection several years previously and diagnosed at that time as adenomatous hyperplasia was re-examined. Nothing about the appearance of this tissue would indicate that carcinoma was to develop in this same gland a few years later. The type of nodular hyperplasia which is most likely to be suspected of being carcinomatous on cursory examination is that in which the alveoli are dilated and contain numerous large, broad and occasional branching papillary projections which sometimes give the impression of secondary alveolar formation. This type of hyperplasia is not uncommon and yet a papillary carcinoma of similar general appearance is rare (only one case in present series) (fig. 4). These facts, namely: (1) that the incidence of benign hyperplasia was practically the same for the control and cancer groups, both for the groups as a whole and when each age group was considered separately, (2) that only a sixth of the cancers in the entire series arose within existing nodular hyperplasias and (3) that no transition could be found between the carcinoma and the benign hyperplasia, coupled with the fact that the gross size of the gland gave no indication of the presence or absence of carcinoma (as shown by comparison of the size of the gland in the presence of localized and unlocalized carcinoma and by comparison of the incidence of nodular hyperplasia as the cause of prostatic hypertrophy in the cases of unlocalized carcinoma and in the control group), indicate that there is no relation between nodular hyperplasia, as such, and carcinoma. Gross asymmetry is of infrequent occurrence when care is taken not to distort the prostate gland during fixation. It was observed in 13 cases in the entire series of glands studied, and only 5 of these glands were carcinomatous. In all of the latter 5 cases the carcinoma involved the entire prostate gland. In the remaining 8 cases the asymmetry was due to the disproportion in size of the nodular hyperplasia in the lateral lobes. It would seem logical to conclude from this that prostatic asymmetry is related to nodular hyperplasia rather than to carcinoma. Sixty-three per cent of the carcinomatous prostate glands showed evidence of inflammation, as did 68 per cent of the controls, indicating that carcinoma is not more frequent in inflamed prostate glands than in those showing no evidence of present or past infection (the inflamma-
570
JAMES E. KAHLER
FIG. 4 upper. Early adenocarcinoma of a papillary type (X85), and lower, benign hyperplasia (X85).
tory reaction immediately surrounding the urethra and larger ducts was disregarded _in estimating inflammation). In those cases in which diffuse acute inflammatory processes occurred, the polymorphonuclear
CARCINOMA OF PROSTATE GLAND
571
exudate showed less tendency to invade the malignant than the benign tissues. Ordinarily, prostatic cancer incites relatively little or no inflammatory reaction. Prostatic epithelium shows less tendency to inflammatory hyperplasia than many other glandular tissues, yet there is a condition associated with chronic inflammation which may sometimes closely resemble early squamous-cell carcinoma, that is, squamous-cell metaplasia. When the latter condition occurs in the depths of the prostate gland, as in one case in the present control group where a small area occurred at a distance of 1.4 cm. from the urethra (direct measurement on the microscopic slide), the differentiation from malignant degeneration must depend on the regularity of the arrangement of the cells, the absence of hyperchromatism, and abnormal nuclear configurations. This type of metaplasia in this series was nearly always associated with some degree of chronic inflammation (fig. 5 upper). It was found to occur in 59 cases (13 per cent) of the control series and was seen in 18 (9 per cent) of the glands which contained adenocarcinoma. It was observed in patients ranging in age from 30 to 91 years and it did not show a predominant distribution in any one age group. The six squamous-cell carcinomas in the series were so advanced that a clear conception of their point of origin could not be obtained and it is therefore impossible to draw definite conclusions as to the importance of squamous-cell metaplasia in the development of squamous-cell carcinoma of the prostate. It may be inferred, however, from the disproportion between the relatively frequent occurrence of squamous metaplasia and the relatively rare occurrence of squamous-cell carcinoma in this organ that the two are probably not related. Only 3 per cent of the carcinomatous prostate glands contained calculi as compared to 13 per cent for the control group. The most marked change directly attributable to the calculi was that seen in one of the control glands which contained the largest stones in the group. Here the lining of the duct containing the stones was composed of 4 layers of flattened cells resembling squamous epithelial cells. It would appear that calculi are practically nonirritating and that, while the metaplasia they produce might conceivably progress to squamous-cell carcinoma, they play no part in the development of adenocarcinoma. It is interesting to mention in connection with calculi that corpora amylacea can be found in the lumina of malignant acini in all grades of adenocarcinoma (fig. 5 lower). The most probable explanation of this phenomenon is that carcinoma cells replace the normal or hyperplastic
572
JAMES E. KAHLER
FrG. S u,pper. Squamous-cell metaplasia in a duct 1.4 cm. from urethra (X48), and lower, corpora amylacea in a grade 2 adenocarcinoma (X95).
lining cells which had originally produced the secretion, later forming the corpus amylaceum. No correlation could be found between the number of interstitial cells
CARCINOMA OF PROSTATE GLAND
573
(estimated number per square millimeter) in the testes and the presence or absence of carcinoma in the prostate gland, either when the cancer and control groups were considered as a whole or when each was subdivided on the basis of age groups and gross size of the gland. SUMMARY AND CONCLUSIONS
This study was based on 195 carcinomas of the prostate gland, of which 72 were diagnosed clinically and 123 at postportem examination. An additional 13.9 per cent of carcinomas were discovered when additional sections, representing a complete cross section of prostate glands, which had been considered benign on the basis of a single routine section, were made. On the basis of this study the incidence of carcinoma of the prostate gland of men more than 50 years of age would appear to be 17.3 per cent. The greater percentage of prostatic cancer is recognizable neither clinically nor on gross examination at necropsy, and a yellow color is of little assistance either as positive or negative evidence in making a gross diagnosis. Leiomyomas, healed infarcts, areas of focal atrophy and chronic hyperplastic inflammatory foci may be mistaken grossly for carcinoma. Carcinoma of the prostate gland does not arise predominantly in any one lobe of the gland; in this study the number of cancers arising in the posterior lobes nearly equalled the number arising in the lateral lobes. No cancer was found to have its origin in the median lobe. The perineural lymphatics were involved in practically all these cases of prostatic cancer, regardless of the size of the tumor or the grade of its malignancy. The involvement of such perineural lymphatics constitutes a reliable criterion for the diagnosis of both early and low-grade malignancy. Fifty-one per cent of the tumors diagnosed clinically or on gross examination at postmortem examination were found to have metastasized. Prostatic carcinomas of the lower grades of malignancy tended to remain localized longer than those of the higher grades of malignancy. No relationship was found between the size of the carcinoma and the incidence of metastasis, and no relationship was found to exist between prostatic carcinoma and associated atrophy, nodular hyperplasia, inflammation, or calculi. Nor was any relationship found to exist between the number of interstitial cells in the testes and the presence of carcinoma in the prostate gland.
5.74
JAMES E. KAHLER
REFERENCES D'ABREU, FRANK: Prostatic epithelial hyperplasia and its relationship to malignancy. Urol. and Cutan. Rev. 40: 12-15, 1936. BARRINGER, B. S.: Carcinoma of the prostate. Ann. Surg. 93: 326-335, 1931. BOTHE, A. E.: Carcinoma of the prostate. Surg. Clin. N. Amer. 9: 1217-1224, 1929. BUMPUS, H. C.: Carcinoma of the prostate: a clinical study. Surg., Gynec. and Obst. 32: 31-43, 1921. CAULK, J. R. AND BooN-lTT, S. B.: Carcinoma of the prostate. Am. J. Cancer 16: 10241052, 1932. COLSTON, J. A. C. AND LEWIS, L. G.: Carcinoma of the prostate: a clinical and pathological study. South. Med. J. 26: 696-703, 1932. DossoT, RAYMOND: Carcinoma of the prostate: its origin and extension. J. Urol. 23: 217245, 1930. FERGUSON, R. S.: Cancer of the prostate: a study of clinical classification and of the effects of treatment by irradiation. Am. Jour. Cancer 16: 783-814, 1932. GERAGHTY, J. T.: Treatment of malignant disease of the prostate and bladder. Tr. Am. Assn. Gen.-Urin. Surg. 14: 117-149, 1921. GERAGHTY, J. T.: Treatment of malignant disease of the prostate and bladder. J. Urol. 7: 33-65, 1922. JOHNSON, F. P.: The later development of the urethra in the male. J. Urol. 4: 447-501, 1920. JUDD, E. S.: Cancer of the prostate. Surg., Gynec., and Obst. 20: 274-277, 1915. MOORE, R. A.: The morphology of small prostatic carcinoma. J. Urol. 33: 224-234, 1935. NELLER, K. AND NEUBURGER, K.: Ueber atypische Epithelwucherungen und beginnende Karzinome in der senilen Prostata. Mtinchen. med. Wchnschr. 1: 57-59, 1926. OERTEL, HORST: Involutionary changes in prostate and female breast in relation to cancer development. Canadian Med. Assn. Jour. 16: 237-241, 1926. RICH, A. R.: On the frequency of occurrence of occult carcinoma of the prostate. J. Urol. 33: 215-223, 1935. TEEM, M. V. B.: Size and weight of the normal and of the pathologic prostate gland. Arch. Path. 22: 817-822, 1936. VAN DuzEN, R. E.: The anatomy of the prostate and vesical neck. South. Med. J. 28: 785-790, 1935. WARREN, SHIELDS, HARRIS, P. N. AND GRAVES, R. C.: Osseous metastasis of carcinoma of the prostate: with special reference to the perineural lymphatics. Arch. Path. 22: 139-160, 1936. WOLFF, RICHARD: Ueber die bosartigen Geschwtilste der Prostata, insbesondere uber die Carcinome derselben. Deutsch. Ztschr. f. Chir. 63: 126-196, 1899. YOUNG, H. H.: Cancer of the prostate: a clinical, pathological and post-operative analysis of 111 cases. Ann. Surg. 60: 1144---1233, 1909.
The morbid anatomist, finding an increasingly higher incidence of clinically undiagnosed tumors of a given organ, is apt to remind the clinician of the need for more accurate study of individual cases. He cannot more than postulate what might have happened had the absence of a lethal lesion permitted the continued growth of the early neoplasm he has discovered. The increasing life expectancy of the human race may eventually raise these early tumors from the realm of purely academic to one of vital economic interest, just as increased curiosity has apparently changed the lesion of prostatic carcinoma from one of uncommon occurrence to one of alarmingly increased incidence in the glands of individuals past middle life. Prostatic carcinoma excites interest clinically, surgically and pathologically because of certain conceptions which have arisen concerning it; namely, that its predominant origin is in the posterior lobe of the gland, that its characteristic color grossly is yellow, that it is closely associated with nodular hyperplasia and atrophy, and that it has a tendency to extend beyond the gland early in its course. These conceptions will be discussed in light of results based on a study of 195 cases of carcinoma of the prostate gland. Materials and methods. The material for this study was comprised of: (1) 141 cases in which a d1agnosis of primary carcinoma of the prostate gland was made in the Section on Pathologic Anatomy at the clinic and (2) fifty-four cases of prostatic carcinoma which were found on examining additional sections of 490 prostate glands, unselected except that the gland had been diagnosed nonmalignant both clinically and on routine macroscopic and microscopic postmortem examination. (The routine postmortem microscopic examination consisted of the study of a single section prepared from a block of tissue approximately 1.5 cm. square taken at random from the gland.) Each gland was accurately measured, its weight calculated and its 1 Abstract of thesis submitted to the faculty of the Graduate School of the University of Minnesota in partial fulfillment of the requirements for the degree of Master of Science in Pathology. 557
558
JAMES E. KAHLER
size classified by the method of Teem. It was opened anteriorly through the urethra and fixed in Kaiserling's solution for a minimum of 4 days. The gland was then sectioned perpendicularly to the floor of the urethra at intervals of 4 mm. Any section grossly suspected of cancer was removed for microscopic study. In the case of glands in which carcinoma could not be detected grossly, a transverse section was selected which would cop.tain tissue from the anterior, lateral and posterior lobes. This section was taken in most instances at or just anterior to the verumontanum. If the median lobe was markedly enlarged, in addition to the routine transverse section, a section was taken through this lobe in the long axis of the urethra. Blocks were embedded in paraffin, cut at 8 microns thickness, and the sections were stained with hematoxylin and eosin. The various lobes of the prostate gland were not found to be demarcated from each other by septa of any kind (Johnson, Van Duzen). For purposes of locating small tumors confined to one lobe, the following landmarks were utilized: the posterior lobe was considered to be that portion of the gland lying posterior to a plane passing through the ejaculatory ducts. If these ducts were not included in the section, which in this case would be anterior to the verumontanum, then everything behind a plane passing through the floor of the urethra was considered to be the posterior lobe. The anterior lobe consisted of the tissue forming the roof of the urethra. The lateral lobes consisted of all tissue lying between the anterior and posterior lobes except the narrow strip of glandular tissue forming the floor of the urethra between the internal sphincter and the verumontanum and known as the median lobe. In some cases large "adenomas" of the lateral lobe compressed the posterior lobe and displaced its tissue so that the tissue of the lateral lobe lay posterior to the floor of the urethra as well as laterally. The posterior lobe was then considered to be bounded anteriorly by a line drawn from the midpoint of the floor of the urethra to the prostatic capsule, and touching tangentially the lower edge of the "adenoma." Figure 1 illustrates this plan of subdividing the transverse sections into lobes. The carcinomas forming the basis of this study may be divided into 5 groups: (1) "clinical carcinomas" or those in cases in which a diagnosis of primary prostatic carcinoma was made before the death of the patient; (2) "routine necropsy carcinomas," or those in cases in which the diagnosis of malignancy was made either grossly during routine postmortem examination or microscopically on examination of the single routine
CARCINOMA OF PROSTATE GLAND
559
microscopic section; (3) "hidden carcinomas," or those not diagnosed clinically or at routine postmortem gross or microscopic examination which were discovered by additional sections prepared for use in this study; (4) "unlocalized carcinomas," or those in groups 1, 2, and 3 in cases in which the neoplasm was too large to be contained within a single lobe of the gland, and (5) "localized carcinomas," or those which, by reason of their size, were definitely restricted to a single lobe of the gland and showed no tendency to infiltrate the remaining lobes and which might therefore be considered as having arisen in the particular lobe in which they were found. lobe~
Post. to verurnontanum
Ant. to ve-rumontanum
Urethra
Pre.seuce of marked nodular hyper>r1o.sio. FIG. 1. Boundaries of prostatic lobes in cross section of gland
Results. Of the 195 prostatic carcinomas in this study, 72 were diagnosed clinically and confirmed at postmortem examination, 69 were diagnosed at necropsy alone, and the remaining 54 were discovered as the result of additional sections of 490 prostate glands previously diagnosed as benign both clinically and pathologically. The 436 glands remaining in this last-named group provided an adequate control series for each decade. In the 72 cases in which prostatic carcinoma was diagnosed clinically, the primary diagnosis was made by palpation alone in 23 cases, was supported by biopsy in 30 additional cases, and in 19 cases was aided by the demonstration of distant metastasis. In only 4 of the cases was a small tumor described clinically; 3 of these tumors proved microscopically to involve the entire prostate gland; the fourth was described as a hard
560
JAMES E. KAHLER
nodule in the left lateral lobe. When the patient came to necropsy, no such nodule could be found grossly; but, microscopically, a small carcinoma about 1 cm. in diameter was found in the left lateral lobe just anterior to the posterior lobe in an area of nodular hyperplasia. All of these carcinomas which were diagnosed clinically with the exception of the one just mentioned were recognized on gross postmortem examination. Twenty-five of them (35 per cent) were described as having a yellowish color; the remainder were described as being white, pink, or grayish-white. At the time of postmortem examination, 30 of the 69 tumors (43 per cent) which had not been diagnosed clinically were grossly suspected of being cancer, 12 because of their yellowish color, 6 because of a white or grayish-white granular mass of increased consistency, 2 because of their hemorrhagic appearance, and 8 because of an increased consistency without any color differentiation from the remainder of the gland. In the remaining 2 cases, small firm yellow areas were found in glands which microscopically proved to be carcinomatous throughout. In 3 additional cases, small yellow areas were described as being suspicious of carcinoma but, microscopically, carcinoma was found elsewhere in the gland. In 39 cases, therefore, the postmortem diagnosis of carcinoma depended entirely on the microscopic findings. Re-examination of the glands permitted a gross diagnosis of carcinoma in only 9 cases, whereas, in 7 others, areas suspected of being cancer because of a yellowish color proved not to be the site of the microscopic carcinoma. All of the 54 tumors found by means of additional sections were sufficiently small to be limited definitely to one lobe of the prostate gland. The largest of these tumors was one occupying approximately half of the posterior lobe, being situated on both sides of the midline and measuring 2 cm. in its greatest diameter. On re-examination of this specimen, the bulk of the tumor was found to be sufficiently far from the capsule to make its recognition by rectal palpation improbable. The peak incidence of carcinoma in both the clinical and routine postmortem groups occurred in the eighth decade, whereas that of the carcinomas diagnosed only when additional sections were made occurred in the seventh decade. The average age at which prostatic carcinoma is recognized clinically is given by various authors as 65 years (Barringer, Bumpus, Caulk and Boon-Itt). The average age for the clinical group in this study was 68.4 years, and that for the routine postmortem group was 68.2 years, thereby reducing this apparent difference considerably.
CARCINOMA OF PROSTATE GLAND
561
So few carcinomas in this series occurred before the age of 50 years that for purposes of calculating the general incidence in the series, only the cases of men 50 years of age or older will be considered. In the period from January 1, 1923 to January 1, 1936, carcinoma of the prostate gland was diagnosed at postmortem examination in 110 cases, or a general postmortem incidence in males 50 years of age or more of 4 per cent. Of the 490 specimens of prostate glands of which additional sections were made, 381 were from men 50 years of age or older and, in these, 53 additional carcinomas were found (13.9 per cent). The expected incidence therefore in a general series in which, as here, entire cross sections of the prostate gland are studied, would be 4 per cent plus 13.3 per cent (13.9 per cent of 96 per cent) or 17.3 per cent in men 50 years of age or older. In necropsies of men more than 50 years of age, Rich, employing a single microscopic section, found 14 per cent carcinomas in 292 consecutive postmortem examinations. (From the illustrations in his article it would appear that some of these sections at least represented a considerable portion of an entire cross section through the posterior lobe and adjacent lateral lobes.) Moore reported 21 per cent carcinomas in a series of 229 men over fifty; he employed step block sections at intervals of 4 mm. It is apparent, therefore, that the number of carcinomas found, particularly in the higher age groups, increases in direct proportion to the number of microscopic sections made in the individual cases. Neller and Neuburger found 25 per cent malignant degeneration in men more than sixty years of age. Moore has also found the same increased percentage of carcinoma with advancing age. In 3 of the cases in which prostatic carcinoma was diagnosed clinically and in 39 of those in which it was discovered first at necropsy, the tumor was small enough to be restricted to 1 lobe of the gland. All of the additional 54 carcinomas found on examining additional sections of tissue were localized in one lobe (table 1). It is apparent from table 1 that less than half of the carcinomas arose in the posterior lobe, a finding which is contrary to that of most authors. It must be admitted, however, that because the amount of technical work was prohibitive, no attempt was made by serially sectioning the remainder of the glands containing these carcinomas to prove that the carcinoma remained localized in the lobe of origin. It is reasonable to assume that serial sections would reveal little or no variation from the present results, particularly in view of the work of Moore which indicates that the general
562
JAMES E. KAHLER
progression of primary prostatic cancer is toward the posterior lobe from the other lobes rather than conversely. As has been emphasized before, in most instances gross inspection is of no assistance in localizing a tumor or in determining its size. No carcinoma was found to have its origin in the median lobe, a result which may be partly explained by the method of taking sections. Carcinoma arising in this lobe is exceedingly rare. Bothe reported 1 case in which cancer arose in the subcervical glands, and Ferguson described 24 instances in a series of 205 cases of prostatic carcinoma in which the tumor involved principally the lobules about the neck of the bladder. None of these tumors, however, was definitely stated to have arisen in the median lobe. Caulk and Boon-Itt demonstrated malignancy in tissue removed by transurethral prostatic resection but gave no further TABLE
1.-Lobe of origin of ninety-six localized carcinomas of the prostate gland LOBE
DIAGNOSED
Anterior
... Clinically .... On routine postmortem examination ........ . . . ...... ...... On re-examination.
Total ..
. . . . . . ..
.
. . . . . . .
.....
Lateral
Posterior
I
Median
2
0
17 28
18 24
0 0
46 (48%)
44 (46%)
0
0
1
4 2 6 (6%)
I
pathologic proof that the carcinoma in any of their cases arose in the glands surrounding the vesical neck. The distribution of the localized tumors in the other lobes would seem to be roughly proportional to the area of these lobes as represented in a cross section of the gland. Eight of these 96 localized tumors appeared to be multicentric in origin. In 5 of them the several malignant foci were all within the posterior lobe; in the remaining 3, the foci were in the lateral lobe, either in normal tissue (in two cases) or in an area of nodular hyperplasia (one case). Only 53 per cent of the entire group of 195 carcinomas were recognized grossly at necropsy. After making a microscopic diagnosis of carcinoma in glands which originally appeared grossly benign a macroscopic reexamination of that portion of the gland known to contain carcinoma revealed the gross lesion at this second inspection in only an additional 7 per cent of cases. Failure to recognize these tumors grossly is therefore due to the absence of characteristics sufficiently distinct to differentiate
CARCINOMA OF PROSTATE GLAND
563
them from normal or hypertrophied prostatic tissue. In general, the characteristics of prostatic carcinoma which permit of its recognition grossly are: its consistency, color and the character of its cut surface. Fifty-one per cent of the tumors were recognized because of increased consistency alone; the remainder were recognized because of a yellowish, white, or hemorrhagic tint, with or without an increase in consistency, or in a few instances because the homogeneous surface of the area contrasted with the porous, oozing surface of the surrounding hypertrophic tissue. None of these characteristics, however, either singly or in combination, are pathognomonic of cancer; increased consistency within the prostate gland was seen also in leiomyoma (two instances) in areas of fibrosis representing, usually, healed infarcts or areas of focal atrophy (seven and five instances, respectively), and in chronic hyperplastic inflammatory processes (seventeen instances). A yellow color has long been considered characteristic of prostatic carcinoma, yet only 21 per cent of the tumors in this series had a yellowish tint. In more than half of these cases, the tissue was homogeneously yellow; in the remainder, yellow streaks were separated by white or semitranslucent bands. A yellowish tint, however, is also seen in tuberculosis and in both acute and chronic pyogenic inflammation of the prostate gland. In 16 cases a localized yellowish area of increased consistency was described grossly for which no microscopic explanation could be found and the carcinoma was discovered in a distant part of the gland where it was not previously suspected. In an additional 6 cases, small yellow areas of increased consistency were seen grossly in glands which microscopically proved to be neoplastic throughout. Sudan III stains on frozen sections indicate that the yellowish tint of prostatic carcinoma is not entirely dependent on the fat content and may therefore be associated with some form of urochrome pigment so prevalent in the urinary tract. Carcinomas of the prostate gland which appear white are most frequently confused with areas of fibrosis or old healed infarcts. The presence of hemorrhage within the tumor is quite misleading and may be simulated by fresh hemorrhagic infarcts. In this connection it is interesting to note that of the control group of 436 cases in which no carcinoma was found, in 62 cases the glands were suspected of containing small early carcinomas because of their gross appearance; microscopically, however, these areas proved to be ones of atrophy, leiomyoma, hyaline fibrosis, inflammation, infarction, and so forth. The suggested classifications of prostatic carcinomas are at present
564
JAMES E. KAHLER
both numerous and confusing. The tumors under consideration were therefore divided into only 2 groups, that is, squamous-cell carcinomas and adenocarcinomas, each group being subdivided according to the grade of malignancy (according to the method of Broders). In this way as satisfactory a mental picture of the microscopic appearance of an individual tumor can be conveyed as by lengthy descriptions. Of the total of 195 tumors, only 6 (3 per cent), were of the squamouscell variety, the remainder being adenocarcinomas. Four of the squamous-cell carcinomas were of grade 2 (on a basis of 1 to 4) ; the remaining 2 were of grade 3. The grade of malignancy of the adenocarcinomas was as follows: grade 1, 19 per cent; grade 2, 50 per cent; grade 3, 27.5 per cent, and grade 4, 3.5 per cent. The incidence of grades 1 and 2 malignancy is greater in localized tumors and in the lower age groups. This suggests that tumors of the lower grades of malignancy tend to remain localized longer than the more malignant ones do. In view of the generally accepted fact that the grade of malignancy of a tumor does not ordinarily change over a period of time, it cannot be concluded that small tumors necessarily grow into unlocalized ones (as there are more unlocalized tumors in the higher grades of malignancy). Similarly, size is not a criterion of the age of a tumor. The microscopic diagnosis of prostatic carcinoma, as for other tissues of the body, depends (among other things) on such criteria as undifferentiation of cells, loss of polarity, and invasiveness and avidity for basic dyes. There is, however, one criterion, which may be peculiar to the prostate gland, that supersedes all others: perineural lymphatic involvement. While extension of a carcinoma to a perineural lymphatic lying in its path is not by any means restricted to prostatic carcinoma, the abundance of sympathetic fibers within and particularly around the prostate gland and the apparently ideal conditions for growth of prostatic carcinomas in the lymphatics surrounding these fibers forms a definite basis for its malignancy. The absence of these lymphatic vessels in some areas of carcinoma is outweighed by the fact of the uniformity of their involvement in the case of tumors of questionable or of a low grade of malignancy. It is particularly in the former group, to which the pathologist alludes as "questionable beginning carcinomas," that the finding of perineural lymphatic involvement is of exceptional value. These cases include those in which the acini are small and lined by low columnar cells with deeply staining nuclei suggestive of senile change, and those in which the acini are larger than normal and the cells definitely
565
CARCINOMA OF PROSTATE GLAND
hyperplastic but in which there is insufficient change to make the diagnosis of neoplasia. Extension to the perineural lymphatics was found in the same lowpower microscopic field as the tumor in 100 per cent of the cases of grades 3 and 4 tumors, in 85 per cent of those of grade 2 tumors, and in 87 per cent of those of grade 1 tumors, or a total involvement of 91 per cent (table 2). In two cases of grade 2 tumors, metastasis was found at a distance of nearly 1 cm. from the tumor. Because of the high incidence of involvement, it is logical to assume that additional sections from the same block of tissue would reveal the extension in a percentage approximately 100 (figs. 2 and 3). TABLE
2.-Perineural lymphatic involvement in adenocarcinoma of the prostate gland
GRADE OF MALIGNANCY
TOTAL NUMBER OF CASES
TUMOR
, I 1
CASES IN WHICH PERINEURAL LYMPHATICS 1NERE INVOLVED ------
---.
per cent
Unlocalized Localized
i
I
3 12
- - ----i--U-n-lo-c-al-iz_e_d_ _ l _ _ _ 33 2 Localized ! 27
TOTAL CASES OF INVOLVEMENT - - - -
per cent
66
87
91 97 70
85
--------1-------- -------- ------·-1---------
3
Unlocalized Localized
34 9
100 100
100
-------1--------1---------------
4
Unlocalized Localized
4
2
-~~~
__I_--=
The localized tumors, many of which were small enough to occupy only 1 or 2 low-power microscopic fields, showed as high an incidence of perineural lymphatic involvement as large tumors involving the entire prostate gland. It is evident, therefore, that local removal of the tumor itself, either by transurethral resection or suprapubic prostatectomy, does not eradicate all of the tumor tissue even in the case of neoplasms of a low grade of malignancy. The demonstration of lymphatic pathways direct to bone rather than to the regional nodes (Warren, Harris and Graves) raises the question as to whether an operative procedure could be made sufficiently extensive to hope to cure the disease. Perineural lymphatic involvement was observed in only 50 per cent of the six squamous-cell carcinomas. This apparent difference between the proportion of adenocarcinomas and squamous-cell carcinomas extending to the perineural lymphatics may be due to a difference in properties
566
JAMES E. KAHLER
FIG. 2 upper. Showing perineural lymphatic involvement in an adenocarcinoma of grade 1 (X85), and lower, showing perineural lymphatic involvement in an adenocarcinoma of grade 2 (X85).
of growth or may result from the smallness of the group of squamouscell tumors observed. Fifty-four (51 per cent) of the tumors recognized clinically or grossly
CARCINOMA OF PROSTATE GLAND
567
FIG. 3 upper. Showing perineural lymphatic involvement in an adenocarcinoma of grade 3 (X48), and lower, showing perineural lymphatic involvement in an adenocarcinoma of grade 4 (X85).
at necropsy had metastasized at the time of the patient's death. In the remaining cases, no unexplained metastasis was found when the prostate gland was not grossly malignant. The most common site of metas-
568
JAMES E. KAHLER
tasis was in the lymph nodes, followed in order by metastasis to the lung, pelvic peritoneum and bone. Microscopic study was not made of bones which were not grossly involved, which accounts for the failure to confirm the work of Warren, Harris and Graves on the extension to bone by way of the perineural lymphatics. Direct extension of the prostatic carcinoma occurred first to the bladder, and then to the ureters, seminal vesicles and rectum, in the order given. It would be expected that tumors small enough to be restricted to one lobe of the gland would exhibit less tendency to metastasize than unlocalized tumors; nevertheless, they too showed a definitely increased incidence of metastasis as the grade of malignancy increased. In the cases of unlocalized tumors, distant metastasis was found in 33 per cent of those of grade 1, in 50 per cent of those of grade 2, in 84 per cent of those of grade 3, and in 100 per cent of those of grade 4. When the carcinomatous prostate glands were divided into localized and unlocalized groups and when each was further subdivided into six subgroups (atrophic, normal and hypertrophic, grades 1 to 4), the number of cancers in each group showing distant metastasis was roughly the same. Thus the probability of metastasis from either large or small lesions bears no relationship to the gross size of the prostate gland. Both atrophy (Rich) and adenomatous hyperplasia have been described as precursors of prostatic carcinoma. While it is impossible to prove that either of these do not represent precancerous lesions, it can be shown that this supposition is illogical. Atrophy within the prostate may be seen in 3 general forms: diffuse senile atrophy, focal areas of atrophy, and atrophy produced by compression of nodular hyperplasia. Atrophy was found in 53.3 per cent of the glands containing small carcinomas and in 53.6 per cent of those in the control group. In studying the individual small tumors, 39.6 per cent arose in normal tissue and 43. 7 per cent in atrophic areas. These figures would indicate that the association of atrophy and carcinoma is an incidental one rather than a causal relationship. Similarly the incidence of nodular hyperplasia in the cancer group was 67 per cent and in the control group 64 per cent. Only 16.6 per cent of the localized tumors were found to arise within areas of nodular hyperplasia. Perhaps of greater significance is the fact that, in this series of cases, no transition could be found between the cancer and the benign hyperplasia surrounding it. In all of the cases in which the carcinoma occu-
CARCINOMA OF PROSTATE GLAND
569
pied a part of the area of nodular hyperplasia, the differences between the 2 types of tissue in the same microscopic field were sharp and distinct. In several cases in which cancer was found at necropsy, tissue removed by transurethral resection several years previously and diagnosed at that time as adenomatous hyperplasia was re-examined. Nothing about the appearance of this tissue would indicate that carcinoma was to develop in this same gland a few years later. The type of nodular hyperplasia which is most likely to be suspected of being carcinomatous on cursory examination is that in which the alveoli are dilated and contain numerous large, broad and occasional branching papillary projections which sometimes give the impression of secondary alveolar formation. This type of hyperplasia is not uncommon and yet a papillary carcinoma of similar general appearance is rare (only one case in present series) (fig. 4). These facts, namely: (1) that the incidence of benign hyperplasia was practically the same for the control and cancer groups, both for the groups as a whole and when each age group was considered separately, (2) that only a sixth of the cancers in the entire series arose within existing nodular hyperplasias and (3) that no transition could be found between the carcinoma and the benign hyperplasia, coupled with the fact that the gross size of the gland gave no indication of the presence or absence of carcinoma (as shown by comparison of the size of the gland in the presence of localized and unlocalized carcinoma and by comparison of the incidence of nodular hyperplasia as the cause of prostatic hypertrophy in the cases of unlocalized carcinoma and in the control group), indicate that there is no relation between nodular hyperplasia, as such, and carcinoma. Gross asymmetry is of infrequent occurrence when care is taken not to distort the prostate gland during fixation. It was observed in 13 cases in the entire series of glands studied, and only 5 of these glands were carcinomatous. In all of the latter 5 cases the carcinoma involved the entire prostate gland. In the remaining 8 cases the asymmetry was due to the disproportion in size of the nodular hyperplasia in the lateral lobes. It would seem logical to conclude from this that prostatic asymmetry is related to nodular hyperplasia rather than to carcinoma. Sixty-three per cent of the carcinomatous prostate glands showed evidence of inflammation, as did 68 per cent of the controls, indicating that carcinoma is not more frequent in inflamed prostate glands than in those showing no evidence of present or past infection (the inflamma-
570
JAMES E. KAHLER
FIG. 4 upper. Early adenocarcinoma of a papillary type (X85), and lower, benign hyperplasia (X85).
tory reaction immediately surrounding the urethra and larger ducts was disregarded _in estimating inflammation). In those cases in which diffuse acute inflammatory processes occurred, the polymorphonuclear
CARCINOMA OF PROSTATE GLAND
571
exudate showed less tendency to invade the malignant than the benign tissues. Ordinarily, prostatic cancer incites relatively little or no inflammatory reaction. Prostatic epithelium shows less tendency to inflammatory hyperplasia than many other glandular tissues, yet there is a condition associated with chronic inflammation which may sometimes closely resemble early squamous-cell carcinoma, that is, squamous-cell metaplasia. When the latter condition occurs in the depths of the prostate gland, as in one case in the present control group where a small area occurred at a distance of 1.4 cm. from the urethra (direct measurement on the microscopic slide), the differentiation from malignant degeneration must depend on the regularity of the arrangement of the cells, the absence of hyperchromatism, and abnormal nuclear configurations. This type of metaplasia in this series was nearly always associated with some degree of chronic inflammation (fig. 5 upper). It was found to occur in 59 cases (13 per cent) of the control series and was seen in 18 (9 per cent) of the glands which contained adenocarcinoma. It was observed in patients ranging in age from 30 to 91 years and it did not show a predominant distribution in any one age group. The six squamous-cell carcinomas in the series were so advanced that a clear conception of their point of origin could not be obtained and it is therefore impossible to draw definite conclusions as to the importance of squamous-cell metaplasia in the development of squamous-cell carcinoma of the prostate. It may be inferred, however, from the disproportion between the relatively frequent occurrence of squamous metaplasia and the relatively rare occurrence of squamous-cell carcinoma in this organ that the two are probably not related. Only 3 per cent of the carcinomatous prostate glands contained calculi as compared to 13 per cent for the control group. The most marked change directly attributable to the calculi was that seen in one of the control glands which contained the largest stones in the group. Here the lining of the duct containing the stones was composed of 4 layers of flattened cells resembling squamous epithelial cells. It would appear that calculi are practically nonirritating and that, while the metaplasia they produce might conceivably progress to squamous-cell carcinoma, they play no part in the development of adenocarcinoma. It is interesting to mention in connection with calculi that corpora amylacea can be found in the lumina of malignant acini in all grades of adenocarcinoma (fig. 5 lower). The most probable explanation of this phenomenon is that carcinoma cells replace the normal or hyperplastic
572
JAMES E. KAHLER
FrG. S u,pper. Squamous-cell metaplasia in a duct 1.4 cm. from urethra (X48), and lower, corpora amylacea in a grade 2 adenocarcinoma (X95).
lining cells which had originally produced the secretion, later forming the corpus amylaceum. No correlation could be found between the number of interstitial cells
CARCINOMA OF PROSTATE GLAND
573
(estimated number per square millimeter) in the testes and the presence or absence of carcinoma in the prostate gland, either when the cancer and control groups were considered as a whole or when each was subdivided on the basis of age groups and gross size of the gland. SUMMARY AND CONCLUSIONS
This study was based on 195 carcinomas of the prostate gland, of which 72 were diagnosed clinically and 123 at postportem examination. An additional 13.9 per cent of carcinomas were discovered when additional sections, representing a complete cross section of prostate glands, which had been considered benign on the basis of a single routine section, were made. On the basis of this study the incidence of carcinoma of the prostate gland of men more than 50 years of age would appear to be 17.3 per cent. The greater percentage of prostatic cancer is recognizable neither clinically nor on gross examination at necropsy, and a yellow color is of little assistance either as positive or negative evidence in making a gross diagnosis. Leiomyomas, healed infarcts, areas of focal atrophy and chronic hyperplastic inflammatory foci may be mistaken grossly for carcinoma. Carcinoma of the prostate gland does not arise predominantly in any one lobe of the gland; in this study the number of cancers arising in the posterior lobes nearly equalled the number arising in the lateral lobes. No cancer was found to have its origin in the median lobe. The perineural lymphatics were involved in practically all these cases of prostatic cancer, regardless of the size of the tumor or the grade of its malignancy. The involvement of such perineural lymphatics constitutes a reliable criterion for the diagnosis of both early and low-grade malignancy. Fifty-one per cent of the tumors diagnosed clinically or on gross examination at postmortem examination were found to have metastasized. Prostatic carcinomas of the lower grades of malignancy tended to remain localized longer than those of the higher grades of malignancy. No relationship was found between the size of the carcinoma and the incidence of metastasis, and no relationship was found to exist between prostatic carcinoma and associated atrophy, nodular hyperplasia, inflammation, or calculi. Nor was any relationship found to exist between the number of interstitial cells in the testes and the presence of carcinoma in the prostate gland.
5.74
JAMES E. KAHLER
REFERENCES D'ABREU, FRANK: Prostatic epithelial hyperplasia and its relationship to malignancy. Urol. and Cutan. Rev. 40: 12-15, 1936. BARRINGER, B. S.: Carcinoma of the prostate. Ann. Surg. 93: 326-335, 1931. BOTHE, A. E.: Carcinoma of the prostate. Surg. Clin. N. Amer. 9: 1217-1224, 1929. BUMPUS, H. C.: Carcinoma of the prostate: a clinical study. Surg., Gynec. and Obst. 32: 31-43, 1921. CAULK, J. R. AND BooN-lTT, S. B.: Carcinoma of the prostate. Am. J. Cancer 16: 10241052, 1932. COLSTON, J. A. C. AND LEWIS, L. G.: Carcinoma of the prostate: a clinical and pathological study. South. Med. J. 26: 696-703, 1932. DossoT, RAYMOND: Carcinoma of the prostate: its origin and extension. J. Urol. 23: 217245, 1930. FERGUSON, R. S.: Cancer of the prostate: a study of clinical classification and of the effects of treatment by irradiation. Am. Jour. Cancer 16: 783-814, 1932. GERAGHTY, J. T.: Treatment of malignant disease of the prostate and bladder. Tr. Am. Assn. Gen.-Urin. Surg. 14: 117-149, 1921. GERAGHTY, J. T.: Treatment of malignant disease of the prostate and bladder. J. Urol. 7: 33-65, 1922. JOHNSON, F. P.: The later development of the urethra in the male. J. Urol. 4: 447-501, 1920. JUDD, E. S.: Cancer of the prostate. Surg., Gynec., and Obst. 20: 274-277, 1915. MOORE, R. A.: The morphology of small prostatic carcinoma. J. Urol. 33: 224-234, 1935. NELLER, K. AND NEUBURGER, K.: Ueber atypische Epithelwucherungen und beginnende Karzinome in der senilen Prostata. Mtinchen. med. Wchnschr. 1: 57-59, 1926. OERTEL, HORST: Involutionary changes in prostate and female breast in relation to cancer development. Canadian Med. Assn. Jour. 16: 237-241, 1926. RICH, A. R.: On the frequency of occurrence of occult carcinoma of the prostate. J. Urol. 33: 215-223, 1935. TEEM, M. V. B.: Size and weight of the normal and of the pathologic prostate gland. Arch. Path. 22: 817-822, 1936. VAN DuzEN, R. E.: The anatomy of the prostate and vesical neck. South. Med. J. 28: 785-790, 1935. WARREN, SHIELDS, HARRIS, P. N. AND GRAVES, R. C.: Osseous metastasis of carcinoma of the prostate: with special reference to the perineural lymphatics. Arch. Path. 22: 139-160, 1936. WOLFF, RICHARD: Ueber die bosartigen Geschwtilste der Prostata, insbesondere uber die Carcinome derselben. Deutsch. Ztschr. f. Chir. 63: 126-196, 1899. YOUNG, H. H.: Cancer of the prostate: a clinical, pathological and post-operative analysis of 111 cases. Ann. Surg. 60: 1144---1233, 1909.