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Precancerous Lesions Of The Prostate
PRECANCEROUS LESIONS OF THE PROSTATE LLOYD
G.
LEWIS,
M.D.*
The Normal Prostate. The development of the human prostate gland from the primitive urethral ducts to the age of puberty is regular and consistent under the influence of the hormones of the testis, in turn stimulated by secretions of the anterior lobe of the pituitary. Certain misconceptions as to embryonic lobe formation should, I believe, be corrected. A study of sections of embryos and of the entire prostate gland of boys up to the age of puberty reveals no lobe formation. The wide variation in the growth and development of the prostate after puberty brings up the question as to what must be considered a normal adult gland. Lobe formation is, I believe, pathologic. Elongation of the prostatic urethra from the verumontanum to the vesical orifice with or without development of fibroadenomatous hyperplasia is quite consistent. In embryos and boys up to puberty the submucosal and periurethral glands of the prespermatic portion of the prostate remain simple and poorly developed while the postspermatic or true prostatic ducts develop into branching complicated glandular structures which make up the bulk of the normal prostate. Whereas the postspermatic glands may undergo cellular hyperplasia, they do not form lobules and are very rarely the site of fibroadenomatous enlargement. Benign Prostatic Hyperplasia. The etiologic factors of benign prostatic hyperplasia are poorly understood. Castration at puberty quite certainly prevents lobular hyperplasia. Undoubtedly the prostate continues to be influenced by testicular hormones after puberty. I have noted rapid benign enlargement of the prostate after removal of a hormone (pragnandiol) producing tumor of the testis, from a 68 year old man, whose prostate had been no larger than one would consider normal for a man of 21 years. When lobular hyperplasia of the prespermatic portion occurs to form the lateral, the subtrigonal, the sub cervical or the anterior commissural lobes, the true prostatic glands undergo displacement and frequently pressure atrophy. CANCER OF THE PROSTATE
The postspermatic or true prostate glands, whose ducts empty into the urethra distal to the openings of the ejaculatory ducts, form the great mass of prostatic tissue in boys at puberty and in adults who have not From the Department of Urology, Georgetown University Medical Center, Washington, D. C. . * Professor of Urology and Chief of Urologic Service, Georgetown University Medical Center and Gallinger Municipal Hospital (Georgetown Division); Consultant in Urology, Walter Reed Army Hospital.
1777
1778
LLOYD G. LEWIS
developed adenomatous hyperplasia. These glands form a lamella extending from the apex of the prostate to its base, almost completely encircling tthe urethra from the anterior to the posterior commissure, being of greatest thickness posterolateral to the ejaculatory ducts. These glands of the true prostate are the common site of carcinoma. Microscopic and occult carcinomas of the prostate have been described in the various prostatic lobes. All authors agree that cancer occurs in over 70 per cent of the cases in the posterior lamella or "lobe." Obviously, it is impossible to ascertain the origin of the cancer when the entire gland is invaded. I have personally examined over 200 prostates removed by total prostatectomy for operable cancer and in every instance carcinoma was found in the posterior lamella. All early lesions were confined to the true prostate gland, either immediately beneath the capsule, or adjacent to the false capsule separating the benign enlargement from the lamella. Early cancer- is more liable to occur in the apical half of the gland. It occurs at the apex or along the lateral border definitely in the lamella. Cancer originating in the tissue of the false capsule could be entirely removed by enucleation of the benign gland, therefore technically one could say the tumor arose in the lateral or median tissues. The cases of Shaw" and of Hinman and Hinman" indicate lesions originating in the septal portions between lobules of adenomatous hyperplasia. There is, in my opinion, no instance of early cancer arising from hyperplastic epithelium. Study of over 5000 prostatic sections has convinced me that hyperplasia and carcinoma of the prostate are totally distinct and separate although frequently concomitant entities. Cytologic Sources of Prostatic Cancer. Only two sources of epithelial tissue for the development of prostatic cancer are definite, the cells of the prostatic acinus and the cells of the ducts. Embryonic rests apparently play no part. . The epithelial cells of the nonhypertrophied prostatic acinus are considered the source in over 95 per cent of cases. According to Moore,' the prostatic epithelium varies from a very high cuboidal in youth to low flattened cuboidal in the senile atrophic prostate. The proliferations of high cuboidal epithelium with papillary structures projecting into the acinus carrying their blood supply in a fibrous tissue stalk, need not, I feel, be considered in the etiology of prostatic cancer. Therefore, we must consider some malignant change of the normal or senile prostatic epithelium as important. If we consider androgens as a stimulant and estrogens as a deterrent to development of hyperplasia, can we also consider them to be factors in the development and control of prostatic cancer? Perhaps an imbalance of the male and female hormones plays a role in the development of hyperplasia. There is no proof that testosterone will cause cancer of the prostate but I believe there is clinical evidence that testosterone stimulates
PRECANCEROUS LESIONS OF PROSTATE
1779
the growth of established prostatic carcinoma. Certainly cancer of the prostate is beneficially influenced by estrogens and by removal of the androgens by castration. The results of treatment of estrogen-resistant prostatic cancer with androgens cannot be evaluated at this time. The fact that the incidence of prostatic cancer increases in the older decades might indicate that degeneration of the glandular epithelium plays a role. Nevertheless, cancer of the prostate has been reported in a boy of 17 by Ewing." I·have observed cancer of the prostate in a boy of 20 and in men of 35, 38 and 42 years of age. In the last three, well differentiated adenocarcinoma was noted; in the youth, undifferentiated tissue, probably arising from prostatic duct epithelium, was found. Adenocarcinoma. Three types of adenocarcinoma are commonly noted. The most common early lesion is made up of tiny proliferating extraacinar structures, lined bya single layer of low cuboidal epithelium, resembling senile atrophic prostatic acini. They must be differentiated by their growth pattern, invasiveness and the cell type. Mitosis and the multinuclear pattern of very malignant cells is usually lacking. These neoplastic acini proliferate, invading the stroma with minute glandular structures which usually lack the basement membrane of normal acini. In very early lesions the hyperplastic acini are not invaded and their cells show no variation from the noncancerous gland. Some pathologists refuse to make the diagnosis of carcinoma because of the lack of cellular criteria but I have seen the development of true cancer of the remaining posterior lamella of the prostate after removal of the benign gland which contained some early neoplastic acini in the tissues of the false capsule in four instances (Fig. 527). Medullary carcinoma is not uncommon. The large acini which would usually represent benign hyperplasia become filled with cancer cells forming tiny pseudo-acini within the larger structure. There is no fibrous tissue stalk nor obvious blood supply. This has been regarded as an invasion of the benign acinus from adenocarcinoma. In many instances, however, the cancer apparently arises from the epithelium of the large acinus to fill the space with medullary carcinoma (Fig. 528). The finding of medullary carcinoma in the testicular metastatic lesion (Fig. 527) is proof that a preexisting dilating acinus is not necessary for the formation of pseudo-acini. Medullary carcinoma and adenocarcinoma are usually found in the same gland. The scirrhous or undifferentiated carcinoma is rarely seen in early lesions. Apparently this is a variation of adenocarcinoma with rapid proliferation so that the whole gland becomes involved before diagnosis is made (Fig. 529). All three types, adenocarcinoma, medullary carcinoma and undifferentiated, may occur in the same gland. They metastasize by invasion of the perineural lymphatics identically and .are undoubtedly variations of the same tumor.
1780
LLOYD G. LEWIS
A
B
Fig. 527. A, Photomicrograph of a microscopic testicular metastatic lesion from carcinoma of the prostate showing in the center tiny neoplastic acini of early carcinoma; to the right formation of pseudo-acini of medullary carcinoma; to the left atrophic testicular tubules. X 125. B, The tiny neoplastic acini to the left are lined by a single layer of low cuboidal cells. Note medullary carcinoma developing in the testicular metastatic lesion. X350.
B A· Fig. 528. A, Photomicrograph of medullary carcinoma of the prostate from an early 5 mm. lesion of the posterior lamella cured by radical perineal prostatectomy. X125. B, Note pseudo-acinus formation. It is apparent that the neoplastic cells are growing from malignant cells lining the large tissue spaces. X350.
'I'ranshional Cell Carcinoma. The' modified transitional epithelium which lines the prostatic ducts from the urethra for a varying distance is undoubtedly the source of carcinoma of the prostate in less than 5 per
PRECANCEROUS LESIONS OF PROSTATE
1781
cent of cases. Proliferation of the duct cell epithelium is common in the presence of infection. Squamous metaplasia occurs quite frequently. It is impossible to state that infection resulting in hyperplasia of the duct epithelium is the cause of cancer. The history of prostatitis in the four cases of transitional cell papillary carcinoma of the prostate which I have studied was not recorded. This type of carcinoma is rarely recognized by digital rectal palpation. Induration, so typical of adenocarcinoma, is usually lacking. Twice I have made the preoperative diagnosis
B
A
Fig. 529. A, Photomicrograph of undifferentiated prostatic cancer in a 20 year old man. At the upper left proliferation and malignant change of the prostatic ducts adjacent to the urethra is noted. X125. B, Infiltrating undifferentiated carcinoma of the prostate. An exception to the rule, this prostate was extremely indurated. Metastases to sternum arid lungs. X350.
of prostatic abscess to find on incision of the prostatic capsule under vision by the perineal route, a soft hemorrhagic grumous material, which, on microscopic section, revealed papillary adenocarcinoma. PRECANCEROUS LESIONS
The microscopic diagnosis of early carcinoma of the prostate is not easy. One should certainly dismiss the possibility of cancer from study of tissues presenting occasional, small acinar structures with intact basement membrane, lined by a single layer of epithelium without evidence of proliferation, but when clusters of these tiny acini are noted, lined by a single layer of low cuboidal epithelial cells, devoid of basement membrane, neoplasia seems obvious. Albarran and Halle' described "epitheliome adenoide" as a cancerous prostatic lesion. They wrote: "In two cases the lesion is in fact early, in the nature of simple adenomatous lobules, fibrous or cystic, which con-
1782
LLOYD G. LEWIS
stitute nearly the whole of the hypertrophied prostate in which one discovers one or two small lobules, well defined, having the typical structure of epitheliome adenoide; tubules entirely glandular, compact, linedwith cylindrical or cuboidal epithelium in many contiguous layers or separated competely by close connective tissue stroma." Young and Davis" felt that epitheliome adenoide represented tangential sections of prostatic acini. I have noted similar arrangement in longitudinal sections of tortuous prostatic ducts and do not feel this lesion represents precancerous or carcinomatous involvement. Proliferation of duct epithelium is common; even proliferation of the acinar epithelium may be noted in the presence of infection or with prostatic calculi. In a few instances the small glandular structures representing compressed acini in the fibrous' stroma of an infarct have been described as malignant. Close examination reveals that these acini are lined by a double row of epithelial cells; the basement membrane is intact and there is no proliferation. It.is most difficult to ascertain malignancy of the prostate from the study of individual cells. It has been said, and I believe rightly, that when there is a question of the diagnosis of malignancy in breast tissue, it is probably benign, but in the prostate it is probably malignant. CONCLUSIONS
There is apparently no well recognized precancerous lesion of the prostate. Carcinoma does not develop in the lobules of benign adenomatous hyperplasia. Any new growth of tissue exhibited by new formation of acini in the posterior lamella or true prostate must be considered malignant. Proliferation of acini lined by a single layer of low cuboidal epithelium suggests the possibility of neoplasia. Hyperplasia results in proliferation of acini lined with a double row of rather high cuboidal or columnar epithelial cells. The diagnosis of malignancy is based on proliferation of new acinar. structures which lack the basement membrane of the normal or hypertrophied acinus. Squamous metaplasia of the ducts or prostatic acini is not uncommon. The low incidence of squamous transitional cell carcinoma of the prostate possibly indicates that we should not consider metaplasia of these cells a precancerous lesion. REFERENCES 1. Albarran and Halle: Annels des maladies des organes genitourinaires 16:797 1898. 2. Ewing, J.: Neoplastic Diseases. 3rd. Ed. Philadelphia, W. B. Saunders Co., 1928, p. 825. 3. Hinman, F., Jr. and Hinman, F.: J. Urol. 62: 723,1949. 4. Moore, R. A.: J. Urol. 33: 224,1935. 5. Shaw, D. C.: J. Urol. 1J..: 63, 1924. 6. Young, H. H. and Davis, D. M.: Young's Practice of Urology. Philadelphia, W. B. Saunders Co., 1927, p. 615.
G.
LEWIS,
M.D.*
The Normal Prostate. The development of the human prostate gland from the primitive urethral ducts to the age of puberty is regular and consistent under the influence of the hormones of the testis, in turn stimulated by secretions of the anterior lobe of the pituitary. Certain misconceptions as to embryonic lobe formation should, I believe, be corrected. A study of sections of embryos and of the entire prostate gland of boys up to the age of puberty reveals no lobe formation. The wide variation in the growth and development of the prostate after puberty brings up the question as to what must be considered a normal adult gland. Lobe formation is, I believe, pathologic. Elongation of the prostatic urethra from the verumontanum to the vesical orifice with or without development of fibroadenomatous hyperplasia is quite consistent. In embryos and boys up to puberty the submucosal and periurethral glands of the prespermatic portion of the prostate remain simple and poorly developed while the postspermatic or true prostatic ducts develop into branching complicated glandular structures which make up the bulk of the normal prostate. Whereas the postspermatic glands may undergo cellular hyperplasia, they do not form lobules and are very rarely the site of fibroadenomatous enlargement. Benign Prostatic Hyperplasia. The etiologic factors of benign prostatic hyperplasia are poorly understood. Castration at puberty quite certainly prevents lobular hyperplasia. Undoubtedly the prostate continues to be influenced by testicular hormones after puberty. I have noted rapid benign enlargement of the prostate after removal of a hormone (pragnandiol) producing tumor of the testis, from a 68 year old man, whose prostate had been no larger than one would consider normal for a man of 21 years. When lobular hyperplasia of the prespermatic portion occurs to form the lateral, the subtrigonal, the sub cervical or the anterior commissural lobes, the true prostatic glands undergo displacement and frequently pressure atrophy. CANCER OF THE PROSTATE
The postspermatic or true prostate glands, whose ducts empty into the urethra distal to the openings of the ejaculatory ducts, form the great mass of prostatic tissue in boys at puberty and in adults who have not From the Department of Urology, Georgetown University Medical Center, Washington, D. C. . * Professor of Urology and Chief of Urologic Service, Georgetown University Medical Center and Gallinger Municipal Hospital (Georgetown Division); Consultant in Urology, Walter Reed Army Hospital.
1777
1778
LLOYD G. LEWIS
developed adenomatous hyperplasia. These glands form a lamella extending from the apex of the prostate to its base, almost completely encircling tthe urethra from the anterior to the posterior commissure, being of greatest thickness posterolateral to the ejaculatory ducts. These glands of the true prostate are the common site of carcinoma. Microscopic and occult carcinomas of the prostate have been described in the various prostatic lobes. All authors agree that cancer occurs in over 70 per cent of the cases in the posterior lamella or "lobe." Obviously, it is impossible to ascertain the origin of the cancer when the entire gland is invaded. I have personally examined over 200 prostates removed by total prostatectomy for operable cancer and in every instance carcinoma was found in the posterior lamella. All early lesions were confined to the true prostate gland, either immediately beneath the capsule, or adjacent to the false capsule separating the benign enlargement from the lamella. Early cancer- is more liable to occur in the apical half of the gland. It occurs at the apex or along the lateral border definitely in the lamella. Cancer originating in the tissue of the false capsule could be entirely removed by enucleation of the benign gland, therefore technically one could say the tumor arose in the lateral or median tissues. The cases of Shaw" and of Hinman and Hinman" indicate lesions originating in the septal portions between lobules of adenomatous hyperplasia. There is, in my opinion, no instance of early cancer arising from hyperplastic epithelium. Study of over 5000 prostatic sections has convinced me that hyperplasia and carcinoma of the prostate are totally distinct and separate although frequently concomitant entities. Cytologic Sources of Prostatic Cancer. Only two sources of epithelial tissue for the development of prostatic cancer are definite, the cells of the prostatic acinus and the cells of the ducts. Embryonic rests apparently play no part. . The epithelial cells of the nonhypertrophied prostatic acinus are considered the source in over 95 per cent of cases. According to Moore,' the prostatic epithelium varies from a very high cuboidal in youth to low flattened cuboidal in the senile atrophic prostate. The proliferations of high cuboidal epithelium with papillary structures projecting into the acinus carrying their blood supply in a fibrous tissue stalk, need not, I feel, be considered in the etiology of prostatic cancer. Therefore, we must consider some malignant change of the normal or senile prostatic epithelium as important. If we consider androgens as a stimulant and estrogens as a deterrent to development of hyperplasia, can we also consider them to be factors in the development and control of prostatic cancer? Perhaps an imbalance of the male and female hormones plays a role in the development of hyperplasia. There is no proof that testosterone will cause cancer of the prostate but I believe there is clinical evidence that testosterone stimulates
PRECANCEROUS LESIONS OF PROSTATE
1779
the growth of established prostatic carcinoma. Certainly cancer of the prostate is beneficially influenced by estrogens and by removal of the androgens by castration. The results of treatment of estrogen-resistant prostatic cancer with androgens cannot be evaluated at this time. The fact that the incidence of prostatic cancer increases in the older decades might indicate that degeneration of the glandular epithelium plays a role. Nevertheless, cancer of the prostate has been reported in a boy of 17 by Ewing." I·have observed cancer of the prostate in a boy of 20 and in men of 35, 38 and 42 years of age. In the last three, well differentiated adenocarcinoma was noted; in the youth, undifferentiated tissue, probably arising from prostatic duct epithelium, was found. Adenocarcinoma. Three types of adenocarcinoma are commonly noted. The most common early lesion is made up of tiny proliferating extraacinar structures, lined bya single layer of low cuboidal epithelium, resembling senile atrophic prostatic acini. They must be differentiated by their growth pattern, invasiveness and the cell type. Mitosis and the multinuclear pattern of very malignant cells is usually lacking. These neoplastic acini proliferate, invading the stroma with minute glandular structures which usually lack the basement membrane of normal acini. In very early lesions the hyperplastic acini are not invaded and their cells show no variation from the noncancerous gland. Some pathologists refuse to make the diagnosis of carcinoma because of the lack of cellular criteria but I have seen the development of true cancer of the remaining posterior lamella of the prostate after removal of the benign gland which contained some early neoplastic acini in the tissues of the false capsule in four instances (Fig. 527). Medullary carcinoma is not uncommon. The large acini which would usually represent benign hyperplasia become filled with cancer cells forming tiny pseudo-acini within the larger structure. There is no fibrous tissue stalk nor obvious blood supply. This has been regarded as an invasion of the benign acinus from adenocarcinoma. In many instances, however, the cancer apparently arises from the epithelium of the large acinus to fill the space with medullary carcinoma (Fig. 528). The finding of medullary carcinoma in the testicular metastatic lesion (Fig. 527) is proof that a preexisting dilating acinus is not necessary for the formation of pseudo-acini. Medullary carcinoma and adenocarcinoma are usually found in the same gland. The scirrhous or undifferentiated carcinoma is rarely seen in early lesions. Apparently this is a variation of adenocarcinoma with rapid proliferation so that the whole gland becomes involved before diagnosis is made (Fig. 529). All three types, adenocarcinoma, medullary carcinoma and undifferentiated, may occur in the same gland. They metastasize by invasion of the perineural lymphatics identically and .are undoubtedly variations of the same tumor.
1780
LLOYD G. LEWIS
A
B
Fig. 527. A, Photomicrograph of a microscopic testicular metastatic lesion from carcinoma of the prostate showing in the center tiny neoplastic acini of early carcinoma; to the right formation of pseudo-acini of medullary carcinoma; to the left atrophic testicular tubules. X 125. B, The tiny neoplastic acini to the left are lined by a single layer of low cuboidal cells. Note medullary carcinoma developing in the testicular metastatic lesion. X350.
B A· Fig. 528. A, Photomicrograph of medullary carcinoma of the prostate from an early 5 mm. lesion of the posterior lamella cured by radical perineal prostatectomy. X125. B, Note pseudo-acinus formation. It is apparent that the neoplastic cells are growing from malignant cells lining the large tissue spaces. X350.
'I'ranshional Cell Carcinoma. The' modified transitional epithelium which lines the prostatic ducts from the urethra for a varying distance is undoubtedly the source of carcinoma of the prostate in less than 5 per
PRECANCEROUS LESIONS OF PROSTATE
1781
cent of cases. Proliferation of the duct cell epithelium is common in the presence of infection. Squamous metaplasia occurs quite frequently. It is impossible to state that infection resulting in hyperplasia of the duct epithelium is the cause of cancer. The history of prostatitis in the four cases of transitional cell papillary carcinoma of the prostate which I have studied was not recorded. This type of carcinoma is rarely recognized by digital rectal palpation. Induration, so typical of adenocarcinoma, is usually lacking. Twice I have made the preoperative diagnosis
B
A
Fig. 529. A, Photomicrograph of undifferentiated prostatic cancer in a 20 year old man. At the upper left proliferation and malignant change of the prostatic ducts adjacent to the urethra is noted. X125. B, Infiltrating undifferentiated carcinoma of the prostate. An exception to the rule, this prostate was extremely indurated. Metastases to sternum arid lungs. X350.
of prostatic abscess to find on incision of the prostatic capsule under vision by the perineal route, a soft hemorrhagic grumous material, which, on microscopic section, revealed papillary adenocarcinoma. PRECANCEROUS LESIONS
The microscopic diagnosis of early carcinoma of the prostate is not easy. One should certainly dismiss the possibility of cancer from study of tissues presenting occasional, small acinar structures with intact basement membrane, lined by a single layer of epithelium without evidence of proliferation, but when clusters of these tiny acini are noted, lined by a single layer of low cuboidal epithelial cells, devoid of basement membrane, neoplasia seems obvious. Albarran and Halle' described "epitheliome adenoide" as a cancerous prostatic lesion. They wrote: "In two cases the lesion is in fact early, in the nature of simple adenomatous lobules, fibrous or cystic, which con-
1782
LLOYD G. LEWIS
stitute nearly the whole of the hypertrophied prostate in which one discovers one or two small lobules, well defined, having the typical structure of epitheliome adenoide; tubules entirely glandular, compact, linedwith cylindrical or cuboidal epithelium in many contiguous layers or separated competely by close connective tissue stroma." Young and Davis" felt that epitheliome adenoide represented tangential sections of prostatic acini. I have noted similar arrangement in longitudinal sections of tortuous prostatic ducts and do not feel this lesion represents precancerous or carcinomatous involvement. Proliferation of duct epithelium is common; even proliferation of the acinar epithelium may be noted in the presence of infection or with prostatic calculi. In a few instances the small glandular structures representing compressed acini in the fibrous' stroma of an infarct have been described as malignant. Close examination reveals that these acini are lined by a double row of epithelial cells; the basement membrane is intact and there is no proliferation. It.is most difficult to ascertain malignancy of the prostate from the study of individual cells. It has been said, and I believe rightly, that when there is a question of the diagnosis of malignancy in breast tissue, it is probably benign, but in the prostate it is probably malignant. CONCLUSIONS
There is apparently no well recognized precancerous lesion of the prostate. Carcinoma does not develop in the lobules of benign adenomatous hyperplasia. Any new growth of tissue exhibited by new formation of acini in the posterior lamella or true prostate must be considered malignant. Proliferation of acini lined by a single layer of low cuboidal epithelium suggests the possibility of neoplasia. Hyperplasia results in proliferation of acini lined with a double row of rather high cuboidal or columnar epithelial cells. The diagnosis of malignancy is based on proliferation of new acinar. structures which lack the basement membrane of the normal or hypertrophied acinus. Squamous metaplasia of the ducts or prostatic acini is not uncommon. The low incidence of squamous transitional cell carcinoma of the prostate possibly indicates that we should not consider metaplasia of these cells a precancerous lesion. REFERENCES 1. Albarran and Halle: Annels des maladies des organes genitourinaires 16:797 1898. 2. Ewing, J.: Neoplastic Diseases. 3rd. Ed. Philadelphia, W. B. Saunders Co., 1928, p. 825. 3. Hinman, F., Jr. and Hinman, F.: J. Urol. 62: 723,1949. 4. Moore, R. A.: J. Urol. 33: 224,1935. 5. Shaw, D. C.: J. Urol. 1J..: 63, 1924. 6. Young, H. H. and Davis, D. M.: Young's Practice of Urology. Philadelphia, W. B. Saunders Co., 1927, p. 615.