Cancer of the Prostate: Its Origin and Extension

CANCER OF THE PROSTATE ITS ORIGIN AND EXTENSION RAYMOND DOSSOT From the Urological Cinic of the Necker Ilospilal, Paris; Professor F. Le11ue1t

In to carry out this work, undertaken at the suggestion of Professor Legueu, I have studied in the Archives of the Clinic, 154 cases of cancer of the prostate, 82 of which were accompanied histological examination of the operative specimen and 63 report. I wish to insist particularly on two points: 1. On relation which exists between adenoma and cancer of the Should one see in the frequent association these two affections merely a simple coincidence, or can trophy degenerate into cancer, thus constituting a preparatory phase of the malignant process'? 2. On precocity of malignant degeneration. Can cancer be recognized at the beginning of its evolution while it is still localized the prostate, and therefore amenable to operation? 1 1 The frequent occurrence of cancer of the prostate is today well known. The following figures are taken from the pathological reports of the clinic from January 1, 1919, to July 15, 1925:

Primary cancer of the prostate 123 Prostatic adenoma .. 557 Cancer of bladder. 99 (68 in the male, 24 in the female, in 7 cases the sex was not given). Cancer of penis. 5 Cancer of testicle. 14 Cancer of urethra. 8 (3 in the male and 5 in the female) Cancer of the kidney. . 48 (22 in the male, 12 in female, and in 14 cases the sex was not given). Thus, A. In the total of 680 prostatic tumors, cancer occurred in 18 per cent. a single case of sarcoma was observed during this period.) * Translated from the French by J. A. C. Colston.

217

(Not

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All of the pathological examinations that I detail have been done by Dr. Verliac. I take pleasure in thanking him for the valuable advice which he has so kindly given me. ADENOMA AND CANCER OF THE PROSTATE

Precancerous states play a very important role in the genesis of cancer. As Mlnetrier has shown, cancer is not a primary morbid entity. It is a result of multiple early and preparatory pathological conditions. In cancer of the prostate some observers have hypothecated the influence of chronic inflammation of the gland, e.g., former gonorrheal infections. It must be recognized that the facts given in favor of this hypothesis are not well founded. On the other hand, the relation between hypertrophy or prostatic adenoma and cancer seem more certain. The older authors, Civiale, Thompson, and Socin suspected this, but the first who showed the frequency of cancer secondary to hypertrophy, and the mode of malignant degeneration, were Albarran and Halle. The histological examination of certain prostates which presented the macroscopic aspect of hypertrophy showed the existence of the epithelial proliferation of evident malignancy. They classed these results in two distinct groups: 1. Adeno-epithelioma, which can be limited, partially circumscribed or diffuse and generalized. The malignant foci are formed by numerous epithelial tubes in close apposition separated from each other by small masses of connective and muscular tissue (fig. 1). 2. Adenoma-epithelioma with epithelial infiltration of the stroma: circumscribed alveolar cancer; around the epithelial lobules cells are infiltrating the stroma. This infiltration shows columns or large groups of cells which fill the alveoli (fig. 8). These diverse results lead to successive degrees of malignancy from benign adenoma to cancer of the prostate. The conclusions B. Cancer of the prostate is by far the most frequent of malignant tumors of the male genito-urinary organs: 123 prostatic cancers, against 112 other localizations, that is, 52 per cent. (If all the cases in which the sex is not given are attributed to the male, one obtains 48 per cent.)

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Albarran and Halle have been accepted by many French and foreign surgeons. However, according to a group of American authors, hypertrophy and cancer of the prostate are two conditions absolutely distinct, which develop each one in a different portion of the

FIG. L

TRUE CANCER OF '.!'HE PROSTATE

Massive infiltration of the stroma by a large number of cellular cords with or without central lumina. The cell-type recalls the normal prostate.

gland; their association is only due to the fact that both develop approximately in the same period of life. According to Young and Geraghty (1911) cancer develops in the posterior subcapsular region in that zone of normal prostatic tissue compressed between the adenomatous masses and the capsule of the gland. When cancer invades an hypertrophied lobe it does so

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RAYMOND DOSSOT

after having invaded the capsule. The picture described under the name of adenoid epithelioma does not correspond to malignant degeneration. It is frequently encountered in chronic prostatitis and in simple hypertrophy (fig. 2). Geraghty, in 1922, in a series of 450 prostatic cancers, noted its association with hypertrophy in 75 per cent of cases, but he in-

FIG. 2.

ADENOMA OF THE PERI-URETHRAL GLANDS

sists on the absolute independence of these two conditions. Clay Shaw, in 1924, states that in more than 1000 operative specimens examined at the Johns Hopkins Hospital, cancer developing in the middle of the hypertrophied lobule has only been found on two occasions, besides which no one has been able to demonstrate the least indication of transition between these two processes.

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In rrsume: In the French conception periurethral adenoma frequently undergoes cancerous degeneration and one finds numerous intermediary stages between benign lesions and malignant lesions. In the American conception, adenoma and cancer co-exist, but have an origin entirely distinct; cancer developing in the prostate only invades secondarily the periurethral adenoma in the same fashion as it spreads to neighboring organs, the bladder for example. That a cancer of the prostate can co-exist with adenoma is not doubted, and we have found many examples of this coincidence, but in the immense majority of cases the theory of Young seems to us untenable. Moreover, malignant degeneration of benign tumors is a generally recognized fact. l'v1enetrier has insisted on the close association of the process of adenomatous hypertrophy and of malignant evolution. The adenoma is a tumor which the process of hyperplasia is individualized in such a manner as to constitute a new organ without function, without utility for the organism to which it is no longer adapted, but with a long life without malignancy. In the transformation adenoma into an epithelioma, one sees the cells proliferate and the adenomatous tubules elongate and grow beyond their normal habitat invading the adjoining connective and other tissues, becoming free to propagate into the interstitial spaces. is characterized only by the accentuation and exaggeration of the phenomena of hyperplasia (figs. 3, 4, 5, 6 and 7). One may observe numerous examples of this degeneration in the organism: transformation of active papillomata, of gastric adenomata, of adenomatous polyposis, of the testis; the intimate relation between cancer and benign tumors of the salivary glands is recognized as well as in the case of the thyroid gland, breast and the kidney. Professor Legueu and Verliac have demonstrated the degeneration of vesical papillomata. alone should prostatic adenoma be an exception to this rule'? On the other hand, it is known that 30 to 50 per cent of prostates undergo adenomatous degeneration. Then if cancer and hypertrophy are only related by mere coincidence, they should be associated with each other in an identical proportion,

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Geraghty himself states that these two diseases co-exist in 75 per cent of cases. Furthermore, a thorough study of microscopic preparations presents the reality of adenoid cancer. It is, in truth, relatively

FIG.

3.

MALIGNANT TRANSFORMATION OF A CYSTIC ADENOMA

At two points (A and B) the glands show destruction of their basement membranes by cells pushing out into the stroma.

easy to find the transition points between epithelioma and adenoma if one studies multiple sections. Let us recall first of all the constitution of the suburethral tumor described under the name of prostatic hypertrophy.

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CANCER OF PROSTATE

This tumor is formed by nodules in juxta-position, some of which are entirely or almost entirely fibrosed and some of which are essentially glandular. The latter are characterized by well developed acini, arranged about an excretory canal. These acini are composed of one or many layers of cells and are always distinctly limited exteriorly by the fibrous and true basal membrane. The lumen is empty or partially filled by a poorly stained

FIG. FIG.

4.

4

FrG

HIGH PowER Vrnw OF SINGLE

Acrnus

5

IN A CASE OF PROSTATIC

HYPERTROPHY

A. Metaplasia of some of the epithelial cells, destruction of the basement membrane and beginning invasive growth. FIG.

5.

Vrnw OF A PORTION OF THE STROMA IN A CASE OF. PROSTATIC HYPERTROPHY

Here one can see early malignant cells beginning to infiltrate the tissue

substance or by detritus. The adenoma can be proliferating: the glandular acini small and numerous, and only separated by thin layers of connective and muscular tissue. Malignant transformation is essentially characterized by the cellular infiltration of the stroma at the periphery of an adenomatous lobule or in the interior of the trabeculae which separate the different lobular elements. One can see aberrant

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cul-de-sacs, small, poorly defined, sometimes open at one or other extremity and proliferating in columns which branch directly in the stroma. This appearance is characteristic and makes one think immediately of cancer.

Fm. 6.

ABOVE, CYSTIC NORMAL AND ADENOMATOUS GLANDS.

BELOW, COMPLETE

NEOPLASTIC DEGENERATION

Examining carefully each section of the preparation the rupture of the basal membrane and infiltration of peri-acinous tissue will almost always be seen. In one or many poi:r;its of the lobule the basal membrane is seen to become less distinct and then to disappear. The epithelial cells form, as it were, a hernia in the stroma and proliferate in the form of a nest or more often stream out between the connective fibers (fig. 4).

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The parts of the adenoma where these transformations are produced can be very numerous so that each one of the adenomatous alveoli seems to transform itself at the time of its constitution. \Vere it not for the fact of the characteristic grouping of the alveoli and the different cellular aspect it would be very difficult to make a differential diagnosis between adenoid cancer and prostatic cancer. In general, the zones of transformation are much less numerous and it is necessary sometimes to search

Fm. 7. Vrnw

SHOWING CELLS GROWING OuT INTO THE STROMA FROM

Acn,r

other sections taken at different points of the tumor in order to find the definitely cancerous parts. The retro-adenomatous layer of the prostate can be healthy or secondarily invaded the neoplasm. Is the definitely malignant aspect always found in adenomata in process of degeneration'? Is not the malignant transformation in certain cases difficult to determine? In consulting the records of the laboratory of the clinic we have determined that often some prostates have been catalogued

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as probable cancerous degeneration; and many of these patients thus catalogued have been found later by us to show a definite recurrence. The appearance of the section which had made Dr. Verliac hesitate in making the diagnosis is the following: around the glandular acini, which seemed to be fairly normal

FIG. 8.

CARCINOMATOUS APPEARANCE OF AN ADENOID CANCER DEVELOPING AT

THE EXPENSF, OF AN ADENOMA THE LOBULES OF WHICH ARE RECOGNIZABLE ONLY IN THE LOWERMOST PART OF THE F IGURE

acini of hypertrophy, are grouped mono-nuclear cells between the fibres of the stroma and simulating nodules of chronic infection ; the presence of a definite limiting membrane at the extremity of the cul-de-sac prevents one being sure of true degeneration, and it is probable that this neoplastic infiltration comes from a

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glandular rupture which has been produced on another plane than that of the section. Whatever may be the interpretation that is given, these portions should be considered as frankly malignant. It is probable that if we had made serial sections we would have been able to follow the steps of the transformation, but we believe that our clinical findings are sufficient to prove our point. Thus, we believe that it is necessary to distinguish two varieties of prostatic cancer; the true cancer of the prostate which develops at the expense of the gland itself; it may co-exist either with or without adenoma; urethro-prostatic adenoid cancer which develops at the expense of the adenomatous glands of the prostatic urethra. Among 134 observations of primary cancer (observations accompanied by pathological examination) we find: 61 urethroprostatic adenoid cancers, 17 adenomata suspected of degeneration (these cannot be proven), 46 true cancers of the prostate, 6 probable true cancers co-existing with adenoma. In 13 cases the nature of the cancer is not specified. Cancer and adenoma were found associated in 58.7 per cent of cases. URETHRO-PROSTATIC ADENOID CANCER

Degeneration of the adenoma is frequent. We have collected from the records of the pathological department of the urological clinic from 1919 to 1925, 557 benign prostatic adenomata and 72 adenomata, either malignant or suspected of malignancy. Malignant transformation of benign hypertrophy occurred in this observation in 11.6 per cent of cases. Adenoid cancers develop in general from adenomata of small or medium size. In 35 cases where the weight of the operative specimen was noted, we find: Less than 8 grams . . . . . . . . . . . . . . . . .. . . .. . . . . . .. . .. . .. . . . .. . . .. . . .. . From 10 to 25 grams ..... . ............... . ......... .... .... ..... .. . From 25 to 50 grams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . From 50 to 100 grams. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Above 100 grams.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (1 case 150 grams, 1 case 205 grams)

8 12 7 6 2

The appearance is that of a simple benign prostatic hypertrophy with one, two or three lobes. However, the irregularity THE JOURNAL OF UROLOGY, VOL. XXIII, NO.

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of the edges and of the surface and the firmer consistence should inspire susp1e10n. The presence of a piece of seminal vesicle torn away in the adenomectomy is also in favor of cancer. But it is especially on section that the suspicions are confirmed. The surface of the adenoma is lobulated. "These lobules of which the limits are more or less indefinite according to the case, are rounded or oval; their average size differs between that of a pea and that of a hazel nut. There are some small ones, also some of larger size and in the same prostate all do not present a similar size. Some have a definite contour appearing isolated from the prostatic tissue by open spaces. Their encapsulation in the surrounding tissue appears all the more distinct because they sometimes bulge out from the surface of the cut section and they may enucleate themselves spontaneously or under the pressure of the finger from the site that they occupy; this enucleation however, being entirely relative. "Others, and this is the more frequent occurrence, have contours less clearly defined, their color, their consistence, especially their spherical appearance and the concentric arrangement of their tissue differentiate them from the neighboring stroma." (Papin and Verliac.)

In malignant transformation the cut section has less of this lobulated aspect which is so characteristic. They become homogeneous at once, finely porous, or granular, but always contain a trace of spheroids. Sometimes the tumor is sprinkled with discrete or confluent yellowish areas which might make one think of suppuration, but on pressure no pus can be expressed. This appearance can be generaliz'ed and simulate a primary cancer of the gland. It is only by the histological examination that the presence of adenoid cancer can be proven. More frequently, (especially in operative specimens), the degeneration is still limited to one lobe, or to one segment of the lobe and it is necessary then to make many sections in order to find a zone of cancerous appearance. In a section of lobulated appearance the hemorrhagic aspect of the lobule is sufficient to reveal the neoplastic transformation. (Verliac). Clinically, urethroprostatic adenoid cancer can have quite

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definite characteristics. The history that is obtained usually is that of a prostatic of long duration who for many years has presented urinary troubles characteristic of benign hypertrophy, nocturnal and later diurnal pollakuiria, slight difficulty in emptying bladder, slight hesitation. At one stage of the evolution these symptoms become aggravated, urination becomes suddenly more frequent, difficult and painful and complete retention or incontinence supervenes in a short time; or perhaps there is a persistent sciatica, repeated hematuria, and then a change in the general condition, a pronounced loss of weight which indicates malignant degeneration. However, in certain cases the evolution proceeds rapidly in a few months as in true cancer of the prostate; either the hypertrophy has not caused any symptoms or the adenoma has degenerated since the beginning of its formation. Examination of the prostate at the beginning of the malignant formation of an adenoma does not furnish any particular information; the gland has conserved its regularity of formation and is elastic and uniform in consistence. In case the patient should present important functional troubles, the finding of a small prostate is particularly to be suspected. It is only in the considerably advanced phase that the hypertrophied prostate becomes hard. The protuberances felt above the gland are indurated vesicles. It is in the late stage also that the cystoscope will show the mucosa around the neck of the bladder irregularly folded and a bas fond which tends to be filled by the elevation en masse of the trigone. All these signs are definite and often the degeneration remains clinically unrecognized, a diagnosis of simple adenoma is made and operation is carried out, but during the prostatectomy the finger does not encounter a plane of cleavage. The tumor is torn out with difficulty, sometimes with a fragment of the vesicles. Several days later the histological examination reveals the true diagnosis. After the intervention the symptoms improve and can even disappear indefinitely. We have observed many cases of cure lasting three, five and six years, More often, after some months or a few years, urinary difficulty reappears, and rectal examination shows that there is no recurrence of adenoma but that a cancer is present.

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In conclusion, periurethral adenoid cancer constitutes a true entity, its location (periurethral), its pathogenesis (degeneration of the adenoma), its shape, its histological constitution, its often definite symptomatology (frequency of the evolution in two periods: a long phase of benign tumor, short phase of malignant tumor), make it possible to distinguish it from true cancer of the prostate. THE PROGRESSION OF CANCER OF THE PROSTATE, ITS COURSE AND EARLY DEVELOPMENT

Cancer of the prostate like all other malignant tumors is primarily an exclusively local disease, but the primary characteristic nodules increase rapidly, invade all the gland and in spreading through the organism by way of the lymphatics or vascular systems extend widely into neighboring organs. It is this essential characteristic which caused Guyon to give it the name of prostato-pelvic carcinosis. It is customary to distinguish two varieties of cancer of the prostate: intracapsular cancer which remains within the limits of the prostatic capsule, and diffuse cancer which tends to invade the whole pelvis. This division is very artificial as by it merely two steps of the cancerous process are separated. We shall see indeed that it is exceptional at autopsy to find neoplasm still limited. We shall discuss successively the peripheral spread and invasion of the glands and the distinct metastases and we shall try definitely to determine at what moment this neoplastic extension is produced; is it early or relatively late? PERIPHERAL ORGANS

Among the diverse lesions that organs adjacent to the neoplastic prostate present, some are due to the mechanical action of the tumor and others to the local extension of the cancer. Seminal vesicles. Cancer of the prostate very frequently extends in an upward and backward direction towards the seminal vesicles. The tumor spreads rapidly toward the intervesicular space, forming an area of induration surrounding and encircling the termination of the vasa deferentia, and the base

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' of the vesicles. The latter become dilated, globular and irregular, thus forming a crescent with a superior concavity which crowns the posterior aspect of the prostate. The enlarged cavities are filled with a liquid of spermatic aspect. Their walls are thickened and sclerosed; microscopic examination reveals no malignant infiltration. It is a question of simple retrograde dilatation. They may exist (as in the case of the patient of Marion, who was the first to emphasize these cases of vesiculitis) while the cancer is still localized to the central portion of the prostate where it compresses the ejaculatory ducts. This compression is produced very early in true cancer of the prostate in which case the place of origin is never very far away from the ejaculatory ducts. Vesicular alteration can occur much later in adenoid cancer, everything depending on the site of the neoplastic transformation; thus vesicular thickening in a prostatic case, if it should make one think of cancer, should not be always interpreted as a sign of certain extension. In the second type which can only occur later, cancer invades the walls of the vesicles. The invasion occurs from within. The adventia can be largely infiftrated without any notable extension into the musculosa or directly into the mucosa. The enlarged and thickened vesicles can remain independent of the prostate or the prostate and vesicles become fixed, forming a single voluminous mass upon the posterior inferior aspect of the bladder. In our 82 operative specimens, in 10 cases the seminal vesicles were torn away with the tumor: 7 times they were invaded by cancer, while 3 times they were not invaded. In 62 autopsies, in 32 cases the condition of the vesicles was noted. Fifteen times they were invaded, 5 times they were invaded and distended, 9 times they were distended (without any other description), 3 times they were not invaded (distended in 2 cases). Bladder. The bladder is most frequently increased in volume. Its internal surface is trabeculated with more or less distinct cellules. This appearance is definite, especially in adenoid cancer. In true cancer of the prostate it is not unusual to find a small globular bladder, retracted, with smooth walls and the vesical neck little deformed.

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The mucosa, in general, is the site of an inflammatory lesion. Infection can invade the whole bladder wall and extend into the perivesical tissue; thus fibro-lipomatous pericystitis in some cases leads to abscess formation. In the 38 autopsies in which the condition of the bladder was specified we find: 21 enlarged trabeculated bladders (10 adenoid, 7 true cancers, 4 cancers of which the nature is not given); 17 small globular bladders (4 adenoid cancers, 2 true cancers, 2 cancers of which the nature is not given). Neoplastic invasion. Invasion of the bladder wall by prostatic cancer is very frequent; 3 types can be distinguished: (1) neoplastic infiltration only disclosed by microscopic examination, (2) tumor formation. In the first stages this is seen only as a simple thickening of the bas fond and of the vesical neck. The trigone is not changed in its dimensions but is a little more elevated and very rigid. Little by little on this firm base small round nodules appear, widely isolated, confluent or cauliflowerlike vegetations, soft red or gray, develop around the ureteral orifices especially posteriorly upwards in the direction of the ureteral orifices which may become partially obstructed. (3) Ulceration of the mucosa. For a long time the changes remain deep, but later the mucosa is invaded from the outside. The vesical neck is transformed into a gaping arid irregular cavity. This last variety of lesion is rare; generally the tumor is already of long duration when the invaded bladder becomes ulcerated and the infection arising in the cavity leads to modification in the structure of the tumor. Histological examination of our operative specimens show in 8 cases cancerous infiltration of the vesical mucosa. In the autopsy reports in three cases the bladder was not invaded. In 2 cases the bladde,:r was invaded histologically. In 24 cases the bladder was invaded macroscopically (in 3 cases neoplastic nodules on the external surface of the trigone, or on the vesical peritoneum; in 3 cases massive infiltration of the trigone; in 15 cases sessile or pedunculated tumor of the bas fond; in 3 cases ulceration of the vesical neck and trigone). Urethra and corpora cavernosa. In true cancer of the prostate

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the appearance of the urethra is entirely different from that which it presents in the adenoid type. In the latter it preserves in general the large dimensions that it has in hypertrophy with all its characteristics: increase in Jength, lateral deviation, elevation of the posterior wall, increase of the anterior posterior dimensions, etc. In true cancer the distance between the orifice and the verumontanum is not changed, at least at the beginning; but the urethral wall becomes rigid throughout or in front and the mucosa, for a long time normal, becomes infiltrated, and diffused with rigid nodules of neoplasm. The mucosa is thickened, congested and friable; this explains the difficulties of catheterization, the hemorrhages which often accompany it and the frequency of false passages. According to the author, involvement of the urethra is rarer than that of the bladder. We have observed it 6 times (that is, in 9.5 per cent of cases)., In none the autopsies has involvement of the corpora cavernosa been noted, but Professor Lequeu has described to us 3 clinical cases of extension of prostatic cancer to the corpora cavernosa. Rectum. Prostatic cancer may extend posteriorly forming a voluminous mass which encircles the rectum but it is rare that it invades the rectal wall. Granulations may appear on the peritoneum covering the pouch of Douglas artd anterior surface of the rectum; but infiltration of the musculosa forming a.n i:n'durated stenosing tumor simulating rectal cancer (as in the case described by Hartmann) or exceptionally an ulceration of the mucosa may occur. (Young in 111 cases has only once seen ulceration of the rectum.) In 63 autopsies involvement of the rectum has been noted 5 times, that is 7 .9 per cent of cases. CELLULAR TISSUE OF THE PELVIS

The cellular tissue of the pelvis is infiltrated by proliferation. of cancerous elements and by way of the lymph channels. Although its extension is most frequently limited to the immediate vicinity of the prostate, in some cases the entire pelvis becomes invaded by an enormous tumor increasing still further in size by the hypogastric glands which fuse with it. Thus occurs the prostato·-pelvic carcinosis: this infiltrated and whitish mass

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RAYMOND DOSSOT

adheres firmly to the bones of the pelvis so that it is necessary at autopsy to actually cut it away in order to remove the pelvic organs. Posteriorly it extends on each side of the rectum compressing the nerve roots of the sacral plexus. It can even extend to the deep regions of the buttocks by passing through the sciatic foramen (Guyon); laterally it becomes adherent to the ischio-pubic rami (to which the cancer extends in some cases), and progressing along the pelvic wall it may encircle the obturator nerves and the iliac vessels; anteriorly it may extend on each side of the bladder up to the pubis. However, there is one direction in which the neoplasm does not extend; that is the perineum which is almost never invaded. We have noted involvement of the pelvis 10 times (15.8 per cent of cases). Prostato-pelvic carcinosis, if one denotes by this name the extension of the tumor throughout the pelvis is then only the natural end result of cancer of the prostate. It seems particularly to be the result of an especially malignant type of cancer of the prostate. In our 10 cases it occurred 5 times in true cancer, twice in adenoid, and in 3 cases the histological nature of the growth was not given. Kidney and ureters. The ureters are often elongated, sinuous and dilated and their thin walls are surrounded by periureteritis; their involvement is extremely rare. The pelvis and calices present similar lesions and are transformed into large cavities which compress the renal parenchyma. Infection is almost always present. The excretory channels are inflamed and filled with pus, the kidneys enlarged and surrounded by a thick layer of fibro-lipomatous perinephritis and are the site of cortical miliary abscesses, or suppurative diffuse nephritis or of sclerosing nephritis. This uretero-pelvic dilatation was noted in 26 of our observations. It is, in general, secondary to vesical distension and retention; 5 times it was due to compression of the ureters in the pelvis by the tumor or by a glandular mass; once to the obstruction of the ureteral orifice by a vesical nodule. In 15 cases the ureters were normal, the kidneys small with atrophy of the parenchyma and lesions of chronic nephritis.

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ADENPOATHIES

Involvement of the glands is a question of very great importance; it constitutes the broadest obstacle to the radical treatment of carcinoma of the prostate. We believe it necessary to recall rapidly the anatomy of the lymphatics of the prostate. Lymphatics of the prostate originate in fine capillary vessels which are disposed about the acini. From these periacinous branches arise larger vessels which extend to the periphery of the gland and form on its surface a periprostatic plexus. These intraglandular vessels are more abundant in the median portion than at the base and apex of the prostate (Caminiti). Besides these, rudimentary lymph nodules discovered by Walker, are present in the gland; they have been studied recently by Nobuyaki Fukase. They occur in the immediate vicinity of the larger acini and excretory ducts. The collecting vessels leave the periprostatic plexus in a systematic fashion for each half of the gland. They take four different directions (Poirier et Cuneo). First, a primary trunk originating in the vicinity of the posterior aspect of the prostate extends on the bladder to the level of the inter-differential triangle towards the mid portion of the posterior superior aspect of the bladder curving in an upward direction and encountering the umbilical artery and terminating in the middle ganglion of the middle chain of the external-iliac group. This ascending channel consists sometimes of two trunks which terminate within the middle and superior ganglion of the middle chain. A second collecting vessel, originating as the first on the posterior aspect of the prostate, accompanies the prostatic artery in its course upwards externally and posteriorly and terminates in one of the middle ganglions of the hypogastric group. Two or three other collecting vessels, also posterior, course in an upward posterior direction crossing the lateral aspects of the rectum mounting over the anterior surface to the sacrum and terminate on the one hand in the lateral sacral ganglion and on the other hand in the ganglion of the promontory. From the anterior surface of the prostate one vessel descends toward the floor of the pelvis, ac-

7

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RAYMOND DOSSOT

companies the urethral artery thence to the internal pubic artery and terminates in a ganglion of the hypogastric group situated along the course of the intrapelvic portion of the internal pudic. Among our observations, in 38 cases the condition and location of theglandswerenoted, 2 and their neoplastic nature has been often verified by histological examination. In two cases only no glands were found; in one case of adenoid cancer which had invaded the seminal vesicles and ulcerated the neck of the bladder, in spite of the absence of glands the pleura was the site of malignant lyrnphangitis which extended to the lungs. The other observation was that of an adenoid cancer which invaded the prostate and vesical wall. In the 36 other cases, in 34 ilio-pelvic glands and in 33 abdominal glands were invaded. Among the ilio-pelvic glands the more frequently invaded were the hypogastric group (21 cases) and primary iliac (20 cases). The external iliac group was less frequently invaded (17 cases), and it is the middle chain of this group which is more frequently involved. In one case there was noticed enlargement of the retro-rectal glands. The enlargement .of these glandular groups is very irregular. One of them can be free from involvement while its neighbor is infiltrated, or indeed on one side can be found a continuous chain from the hypogastric to the primary iliac, while on the other hand often only a few external or common iliac glands will be found invaded. All the abdominal glandular groups can be invaded both pre- and retro-aortic, left juxta-aortic, right juxta-aortic, pre- and retrocaval, but rarely the involvement extends above the renal vessels. In one case the tracheo-bronchial glands from the trachea to the hilum of the lung were cancerous. The right lung presented neoplastic granulations. Supraclavicular adenopathy was noted in no case. We have observed it clinically in one case on the left side (true cancer of the prostate with spinal metastasis). Involvement of the inguinal glands occurred only in 3 cases (twice bilateral, once on a single side). This percentage is distinctly less than that indicated by other writers. The involve2 The site of glandular involvement has been very exactly noted, aside from the autopsies, by tables originated by M. Verliac.

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CANCER OF PROSTATE

ment of these glands is moreover difficult to explain as the prostatic lymphatics are not tributary to this glandular group. Extension of cancer of the urethra to the corpora cavernosa and to the perineum has been explained by the lymphatic relation with the inguinal regions, but we have seen how rarely inguinal envolvement occurs; therefore, one is forced to admit the reflux theory (Broca, Jolly); efferant vessels of vessels primarily involved are obliterated by the malignant induration and there is then a reflux of lymph, stopping in its forward progress in the subjacent ganglion. In one of our cases histological examination showed sclerotic lesions without trace of neoplasm. This simple adenitis is much more easy to explain; prostatic cancer is always accompanied by an infectious process, which involves the tumor and all the peripheral structures. Perhaps the inguinal adenitides which have been noted are frequently of inflammatory origin, but this point can be elucidated only by further studies. The frequency and location of adenopathies observed in our personal cases are indicated in the following table: Cases Per cent

Number of cases . . . .. . .. . . .... . ...... . ... . . . .. . .. Cases without adenopathy... .. . . . . . . . . . . . . . . . . . . Hypo-gastric glands .. . ..••....... . .... . .. ... . . . . External iliac glands. . . . . . . . . . . . . . . . . . . . . . . . . . . . Primary iliac glands .. .. . .. ... . ........ . ... .. . . . . Pelvic glands without other specifications. .... . .. Abdominal glands ... . . . . . .... . . ... .... .. . .. .. . . . Inguinal glands.......... . ... . ...... . . . ... ... . . .. Tracho bronchial glands. . .. .. . . . . . . . . . . . . . . . . . . . Supra clavicular glands... ... . . .... ...... .... ... .

38 2 5.2] 55. 2 34 cases21 44. 7 89. 4 per 17 50 cent 20 13 5 86.8 33 3 1 1 (clinical case)

Cancerous glands are increased in size, hard on section, white, with a homogeneous aspect. More frequently they are without periadenitis and they would easily pass unnoticed if one did not search systematically in the cellular tissue in the pelvis and along the course of the large abdominal vessels. However, sometimes an intense periadenitis surrounds them and involves them all, and they form an enormous neoplastic mass filling the entire pelvis or forming a thick prevertebral area of infiltration which

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can be the point of origin of spinal invasion. We have observed this latter variety 12 times : 8 times in true cancer of the prostate, twice in adenoid cancer and in 2 cases the nature of the cancer was not given. METASTASES

Visceral metastases are infrequent. They were only noted in 9 of our observations on 63 autopsies (14.2 per cent); 7 pleuropulmonary, 2 hepatic. They seem to be more frequent in true cancer of the prostate (4 cases), than in adenoid cancer (2 cases) . They occur through the blood stream and through the lymphatics. Bone metastases. Although visceral metastases are rare in cancer of the prostate, bony metastases are frequent.3 They were noted for the first time by Thompson. A few isolated cases were then reported (Silcock, Forster), but it was Recklinghausen, who with 5 personal cases made the first complete study. Since then many observations have been published. Kaufmann, in 22 personal cases of cancer of the prostate, found bony metastases 16 times. Motz and Majewski in 26 cases found many times invasion of the bones of the pelvis, 4 of the spinal column and one femoral metastasis. Bumpus, carrying out systemmatic radiographic examination of his patients, found metastases in 30 per cent of cases. Herbst and Thompson observed them in 33 per cent of cases. Today cancer of the prostate is considered after cancer of the breast as the most frequent source of bony metastases. Oppenheim, in 32 cases of vertebral cancer, found 18 breasts, 5 prostates, 4 lungs, 3 thyroids, one kidney and one pancreas. Metastases occur especially in the vertebral column (lumber portion) and bones of the pelvis, after which come the long bones (femur), the skull and the ribs. No osseous metastasis has been noted in the autopsy protocals that I have studied; they are not 3 Here it is only a question of so-called true metastasis, that is to say those cases in which there has been transplantation from a distance of neoplastic cells. From this type it is necessary to separate those in which there has been invasion of bone by contiguity and by direct extension of the tumor, whether it is a question of the primary prostatic tumor or of a secop.dary glandular tumor developing in the neighborhood of the bone.

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evident and pass unnoticed if one does not search for them systematically. The autopsy records show the extreme frequency of neoplastic spread, and in no case have we found the cancer limited to the prostate; always it has invaded the neighboring organs or the glands. One point remains to be emphasized; at what period in its evolution does cancer disseminate? Does it remain for a long time locali'zed to the gland, therefore removable, or on the contrary do the neoplastic cells diffuse early? It is necessary to admit that this question is difficult to solve. We can, however, rely upon certain autopsy studies carried out on patients dying as a result of operation. The clinical diagnosis had been that of an adenoma, and only the examination of the operative specimen revealed the malignant nature of the tumor. It seems to us that one can consider these cases as recent. Case 79 (4837). Resume: Urinary symptoms began six months before arrival at Necker hospital (dysuria, hematuria); clinical diagnosis : infected adenoma. Suprapubic prostatectomy. Death ten days later. At autopsy a prostatic cancer extending to the vesicles was found with numerous neoplastic pelvic and abdominal glands. Case 85 (4878) . Suprapubic prostatectomy for prostatic adenoma. Death ten days later. At autopsy prostatic cancer involving the left seminal vesicle and nearby tissue (no mention of glands is made). Case 96 (5011). Resume: Clinical diagnosis: adenoma; at operation cancer was recognized. Death eight days later. At autopsy an adenoma undergoing malignant degeneration was found which infiltrated the entire organ; involvement of pelvic and abdominal glands. Case 98 (5022). Resume : Suprapubic prostatectomy for adenoma. Death one month later. At autopsy cancer involving the base of the vesicles was found with numerous iliac and abdominal glands. Case 117 (5249). Resume: Prostatic hypertrophy, operated in two stages. Death ten days after prostatectomy. At autopsy the base of the bladder was invaded by cancer which surrounded the seminal vesicles; numerous ilio-pelvic and abdominal glands.

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Thus, in five cases nothing in the clinical examination had been found to suspect neoplasm. Rectal examination had not revealed the slightest irregularity or the slightest indurated area in the prostate (and this is, as one knows, the most constant and earliest sign of cancer). The diagnosis of benign hypertrophy was made but nevertheless in all these cases the tumor had already extended beyond the limits of the gland and invaded the pelvic and abdominal glands (with exception of case 85, in which the condition was not noted). From the study of these facts we believe it necessary to conclude that prostatic cancer, true cancer and adenoid-cancer, extend very readily to nearby organs and tha:t malignant degeneration occurs very early. Thus is explained the numerous disappointments which the surgeon and radio therapeutist experience in the treatment of malignant tumors of the prostate. THERAPEUTIC DEDUCTIONS

One can classify the results of the different methods utilized in treatment of cancer of the prostate in the following manner: Surgical interjerence. The radical prostatectomy, Young technique, has a high mortality, is often followed with fistula or partial or total incontinence; its late results are very mediocre and cases cured more than three years are the exception. Radium therapy. This is evidently less hazardous but it is nevertheless not without danger; proctitis, recto-vesical perforation (Andre, Marion), urethral reactions, hematuria, incontinence, intestinal accidents (Gayet, Verliac) evidences of systemic intoxication, and venous thrombosis (Gayet) have occurred. Radiations have a certain action on malignant cells of the prostate: the tumor diminishes in size, becomes less indurated and more pliable, and the functional symptoms are generally improved, but over a long duration of time good results are very rare and a certain number of them are still doubtful on account of the fact that histological examination is lacking. Deep radio-therapy has as yet been too little used for one to judge accurately about its efficacy. The association of surgery and radiation (application of radium

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before or after prostatectomy) is advised by many urologists, but here again recurrence is the rule. These results are frankly mediocre. There is nothing in this which can surprise us since any therapy directed against cancer should be able to destroy completely the neoplastic cells and we only have at our disposal, whether it is a question of surgery or radium, only a method applicable to local action which cannot have any effects once the tumor has spread. Pathological anatomy shows us the frequency of dissemination in prostatic cancer. It is only in its earliest stage, when it is still strictly localized to the gland, that one can attack it with any chance of success. Unfortunately, at this period either the patient does not come for consultation or the physician can find no sign which will permit him to make a diagnosis of malignant tumor. In the great majority of cases when cancer on palpation shows signs characteristic enough to make the diagnosis certain it has already progressed extensively to nearby organs and to the glands. One can only hope to have cures in those patients operated for a benign_hypertrophy in whom histological examination demonstrates the existence of the malignant tumor. Observations have been made on 28 results of suprapubic prostatectomy done by P rofessor Legueu under such conditions: of these 28 patients, 9 are dead. 1 patient 4½ years after operation 1 patient 1 year after operation 1 patient 16 months after operation 2 patients 2 years after operation 1 patient 10 years after operation 3 patients-no information on date of death. 19 were living in July, 1925. In 12 of them cure had been maintained since Number of cases

6½ years . . . . _... . ..... . . . . . .. . . . . ... .. . ... . . .. . . .. . .... .. . ... . . . .. . . . 5½ years . .. .......... . . .. ... . . . . ........ . .... . . .. .. . .. . . . . .. ... . ... .. 2 years 8 months . . . . ... ..... . .... .. ... . . . ... . . .... .. ... . .... . .. . .... 2 years . . . ....... . ... .. .. .... . . .. . .. . . . .. . ..... .... .... ... . . . .. . . .. . . 20 months . . .... . .. .. . . .... . .. ..... . . .... . . . . . ... . . . . .. .. . . .. . . .... . . 19 months . . . . . ...... .. ,, . ... .. ... . . .... .... . ... . .. .. . .. . .... . .. ..... 18 months ....... . . . . .. ... . . . .. ... ... . ............. .. ... . . .. . . ... . . . . 17 months .. .. .. . .. .. . . . . . . . .. .... . . .. .. ....... .. .. . .. . . . ....... . .. ..

1 1 2 2 2 1 1 2

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Examination showed in 6 cases urethro-prostatic adenoid cancer; in 4 cases adenoma, one adenoma suspicious of degeneration; in 2 cases true cancer of the prostate. The 7 remaining cases have very probably recurred: 5 years, 2 years 7 months, 2 years 18 months, 17 months, 16 months and 8 months after intervention. A diagnosis of adenoid cancer was made 5 times, adenoma suspicious of degneration twice, true cancer of the prostatE) once. Suprapubic prostatectomy carried out very early is therefore capable of giving some interesting results over a long period of time, not only in adenoid but also in true cancer of the prostate (survival 6½ years and 2 years 8 months). The immediate mortality is scarcely higher than in the removal of benign hypertrophy. Among 51 operations carried out under such conditions at the Necker clinic from 1919 to 1925, there were six deaths, that is 11.7 per cent mortafity. The postoperative results are satisfactory. Professor Legueu has observed only one complication which was moreover only temporary: one patient presented, as a result of removal of the prostate and seminal vesicles, a complete incontinence, absolute and total; this incontinence however lasted only one month and little by little satisfactory control returned. It can therefore be concluded that the appearance of symptoms, which might lead one to suspect a malignant tumor or the degeneration of a hypertrophy (rapidity of development, sudden aggravation of symptoms and changes in the general condition), is a definite indication for intervention. Moreover, by prostatectomy a true prophylaxis of cancer is realized. When the histological examination has shown the existence of a malignancy should one make an application of radium in the vesico-prostatic cavity? Opinions are divided on this subject. It seems indeed that the results of this association of therapy are not better than those obtained by surgery alone. It is necessary now to consider those cases in which cancer of the prostate has been diagnosed clinically. Professor Legueu, with whom the majority of surgeons are in agreement, has entirely given up total prostatectomies and partial operations. Radium, hailed as a method of radical treatment, has indications which are distinctly limited; in this stage cancer has already in-

~l,I

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vaded the pelvic and abdominal glands and it is impossible to radiate the whole of the tumor. Indeed, as Regaud has noticed, when in place of radiating the whole extent of the cancerous area one radiates only one part there occurs an extension of the growth into the portions not radiated. It seems that when the organ harbors a large cancer and when a portion of this has been removed either by surgery or by radio-therapy there occurs a too brusque rupture of equilibrium in the nutritional power of the organism. This rupture of equilibrium is followed by a rapid growth. It is therefore wise at the present time to limit oneself, in the very great majority of cases, to an entirely palliative therapy; passage of sounds, bladder irrigations and if the instrumentation is difficult or if the patient presents retention with distention, cystostomy. CONCLUSIONS

' -~'

1. Prostatic adenoma plays an important role in the pathogenesis of numerous cancers; in 11.6 per cent of cases it undergoes malignant transformation. Two types of prostatic cancer should be distinguished; urethroprostatic adenoid cancer, which develops from the adenomatous glands of the prostatic urethra, and true cancer of the prostate which develops from the prostate itself. The latter may coexist with an adenoma. Cancers and adenomata are associated in 58. 7 per cent of cases. 2. Invasion of nearby organs and lymph glands always occurs in cancer of the prostate. These extensions are very early, and before they can be recognized clinically the cancer has extended widely past the limits of the gland and has invaded the pelvic and abdominal lymph glands. 3. Prostatectomy, radium therapy and radio-therapy have only given very mediocre results and cases remaining cured for more than 3 years are the exception. True cures can only be obtained in those patients operated with a diagnosis of adenoma in whom histological examination shows the existence of cancer. When cancer has progressed sufficiently to be recognized it has, generally speaking, extended widely. Therefore, it is prudent at the present state of our knowledge to limit our efforts to palliative therapy; passage of sounds and cystostomy.

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REFERENCES ALBARRAN ET HALLE: Hypertrophie et neoplasies epitheliales de la prostate. Ann. des Mal. des Org. Gen. Urin., 1906, 113 et 225. ALBARRAN ET HALLE: Hypertrophie et neoplasies epitheliales de la prostate. Ann des Mal. des Org. Gen. Urin., 1898, 797. ANDRE: Le traitement du cancer de la prostate par le radium. Bull. Soc. Fran9. d'Urologie 1923, 46. BUMPUS: Carcinoma of the prostate. Surg. Gynecol., and Obstet., 1921, xxxii, 31. BUMPUS: Radium in cancer of the prostate. A report of two hundred and seventeen cases. Jour. Amer. Med. Assoc., 1922, 1374. BuMPus: Surg., Gynecol., and Obstet., Aollt 1926. DossoT, R.: Le Cancer de la Prostate. Etude Anatomique, Clinique et therapeutique. These Paris, 1926. DossoT, R .: Les origines et les Extensions du Cancer de la Prostate. Archives Urolog. de la Clinique de Necker, T . V., fasc. 4, 257. GAYET, BERARD: Quelques dangers des applications de radium pour cancer de la prostate. Soc. Chir. de Lyon, 6 Mars 1924. GAYET ET PEYCELON: Contribution al' etude du traitement du cancer de la prost ate. Ann. Franco-Belges de Chir., Sept., 1925. GERAGHT-Y:, J. T.: Treatment of malignant disease of the prostate and bladder. Trans. Amer. Assoc. Gen. Urin. Surg., 1921, 117. GUYON, F.: Carcinose prostato-pelvienne diffuse. Le9ons clin. sur les affections chirurgicales de la vessie et de la prostate, 1888, 1049. GUYON, F. : Bull. Soc. Anatomique, Paris, 1856, 456. HALLOPEAU: Les tumeurs malignes de la prostate. These Paris, 1906. HARTMANN, H.: Cancer de la prostate simulant un cancer du rectum. Travaux de Chir. Anatomo-clinique, 1913, 204. JOLY, J.: Essai sur le cancer de la prostate. Archives Generales de Medecine, Mai, 1869. LEGUEU, F . : Bull. Soc. d'Urologie, 1919, 140. LEGUEU, F.: Traite Chirurgical d'Urologie, 2:me Edition, 1921, 1300. LEGUEU, F . : Bull. de la Soc. Fran9. d'Urolog., 1922, 188. LEGUEU, F . : Traitement du cancer de la prostate par le radium. Bull. Soc. Fran9. D'Urolog., 1923, 98. LEGUEU, F . : Les infections de l'adenome prostatique. Monde Med., 15 Mars 1925, 297. LEGUEU, F . ET MOREL: Valeur de l'eosinophilie dans le diagnostic des affections chirurgicales de la prostate. Archiv Urolog. de la Clinique Necker, T . I., 295. MARION: De la signification des vesiculites chroniques chez les prostatiques. Journ. d'Urologie, T. IX, 1920, 11. MARION: De la signification des vesiculites chroniques chez les prostatiques. Bull. Soc. Fran9. d'Urol., 1919, 140; 1920, 99. MARION: Apropos du traitement du cancer de la prostate. Journ. d'Urologie, T. XXI, 1926, 385. MENETRIER : Cancer (in Traite de Med. et de Therapeutique. Gilbert et Thoinot) 1909.

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MOTZ ET MAJEWSKI: Contribution a l'etude anatomique et clinique des cancers epitheliaux de la prostate. Ann. des Mal. des Org. Gen. Urin., 1907, 161. OPPENHEIMER: Early symptoms of spinal cancer. Jour. Bone and Joint Surg., 1922, xx, 342. ORAISON: Cancer de la prostate et radium. Bull. Soc. Fran9. d'Urol., 1922, 209. PAPIN: Traitement du cancer de la prostate par la radium. Bull. Soc. Fran9 . .,·,,~ d'Urolog, 1923, 22. P ASTEAU, 0 . : Etat du systeme lymphatique dans !es maladies de la vessie et de , ~ .; la prostate. These Paris, 1898. PASTEAU, 0.: Traitement du cancer de la prostate par le radium. Bull. Soc. Fran9. d'Urol., 1923, 70. PAUCHET: Pratique chirurgicale illustree, viii, 124. REGAUD: Fondements physiologiques de la radiotherapie des cancers. Paris, 1925. SHAW, CLAY E . : An early case of carcinoma of the prostate associated with benign hypertrophy. Jour. Urol., January, 1924, xi, 63. SocIN, A., ET BuRCKHARDT, E.: Die Verletzungen und Krankheiten der Prostata. Stuttgard, 1902, 374. Socrn, A. : Handbuch der Chirurgie (Pitha und Billroth), T . III, 1875. VERLIAc : Traitement du cancer de la prostate par le radium. Bull. Soc. Fran9. d'Urol., 1923, 25. YOUNG, H . : The early diagnosis and radical cure of carcinoma of the prostate. Johns Hopkins Hospital Reports, XIV, 1906, 485. YOUNG, H .: The application of perineal prostatectomy to carcinoma of the prostate and chronic prostatitis. Trans. Amer. Assoc. Gen.-Urin. Surg., 1907, 78. YouNG, H. : Cancer of the prostate. Ann. Surg., December, 1909, 556. YOUNG, H . : Le cancer de la prostate. Analyse clinique, anatomopathologique et post-operatoire de 111 observations. Ann. des Mal. des Org., Gen. Urin., 1910, 1743, et 1840. YouNG, H. : Diagnostic et traitement du cancer de la prostate au debut. Rap. Congres Int. des Scienc. Medic., Londres, 1913. YOUNG, H .: The diagnosis and treatment of early malignant diseases of the prostate. Amer. Jour. Urol., 1914, T. X, 251. YouNG, H .: Practice of Urology, 1926.