L
Vol. 113, February Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1975 by The Williams & Wilkins Co.
MORPHOGENESIS OF NODULAR HYPERPLASIA-PROSTATE B. K. PRADHAN
AND
K. CHANDRA*
From the Department of Pathology, Maulana Azad Medical College and Irwin & G. B. Pant Hospitals, New Delhi, India
The etiology and morphogenesis of prostatic nodular hyperplasia, a common disease of elderly men, have been subjects of controversy for decades. Many theories have been proposed to explain the morphological patterns in the evolution of nodular hyperplasia. However, there still exists much speculation as to the relationship among the pure fibrous nodules, the pure glandular nodules and the mixed varieties. We have studied the incidence and morphological evolution of nodular hyperplasia by the stepsection technique, using material collected from the apparently asymptomatic population as represented in the medicolegal deaths autopsied. MATERIAL AND METHODS
Prostates were removed from 161 autopsy cases in 1 piece with the bladder and rectum. The complete prostate was then dissected and separated from the surrounding tissue. To facilitate deeper penetration of the preservative 1 or 2 cuts were made (depending on the size of the prostate) in transverse direction to the long axis of the gland. The prostate was preserved in 10 per cent buffered formalin for 24 to 48 hours, after which a detailed gross examination was done and sections were made. A rough outline of the complete gland was traced on paper to record an impression of its size, site of nodularity and asymmetry. The gland was then divided transversely into sections each 0.4 cm. apart. The sections were numbered starting from the superior end and proceeding toward the inferior end, each section representing a transverse section of the complete gland. After the tissues were embedded, the paraffin blocks, thus prepared, were cut from the superior aspect of each so that the sections from subsequent blocks were separated from each other roughly by 0.4 cm. All sections were stained with hematoxylin and eosin. Special stains for collagen, smooth muscle and elastic tissue were prepared when indicated. OBSERVATION
The age of patients from whom the prostates were taken ranged from newborn to 85 years. The cases were grouped in decades and the range of weights were noted (table 1). The prostate having maximum weight of 51 gm. was from a 70-year-old subject. Accepted for publication May 31, 1974. * Requests for reprints: Department of Pathology, Maulana Azad Medical College, New Delhi-1, India. 210
A naked eye examination of prostates in nodular hyperplasia revealed mild to moderate enlarge- · ment of the gland. Nodularity on the external surface was usually located laterally or anterolaterally and was noticed in 9 of 54 prostates from patients more than 40 years old (16.5 per cent). The cut surface of the prostates in nodular hyperplasia revealed nodules varying in size from 0.2 to 1.0 cm. in greatest dimension. They were well circumscribed, rounded areas in sharp contrast to the uniform, gray, homogeneous, glistening and firm normal prostatic tissue. Some nodules had a honey-combed appearance. Nodules on cut surface were seen in 20 of 54 prostates from patients more than 40 years old. The numerous nodules of varying size on cut surface produced compression and distortion of the urethra in several prostates (fig. 1). Microscopically a nodule was characterized by localized' proliferation of fibrous tissue, muscle tissue, glandular elements or their combination, with evidence of centrifugal expansion within the nodule producing obvious compression of the surrounding stroma or epithelial elements. Several types of nodules were recognized. Early nodule. An early nodule was recognized as a stromal focus of pale stained tissue, which in most cases was well circumscribed. In a few early nodules the nodular tissue at the periphery appeared to be merging into the surrounding stroma, thereby making the outline poorly defined. Most early nodules were close to or at some distance from the urethra. Some were in the middle zone of the prostate in close relation to the ducts and an occasional one was in the outer zone. A few stromal nodules were close to the prostatic utricle. Several types of early nodules were recognized. Pure stromal nodule: Stromal nodules were clearly distinguishable from the surrounding tissue by their loose texture and pale staining (fig. 2). They were composed of spindle cells with a round to oval nucleus, the chromatin of which was distributed evenly, giving a light staining reaction. The cytoplasm was lightly eosinophilic. The intercellular space was adequate and fibrillar in appearance owing to cytoplasmic processes extending from contiguous cells. The cytoplasm of the cells within the nodules took a positive stain for collagen. In contrast to this, the surrounding normal prostatic tissue was composed of spindle cells with elongated nuclei and tapering ends. The nuclei were densely chromatic and the cytoplasm was deeply eosinophilic. The intercellular substance contained an adequate amount of collagen. By van
MORPHOGENESIS OF NODULAR HYPERPLASIA-PROSTATE TABLE
1. Weight of prostate in grams and number of
cases according to age groups
Groups (yrs.)
Age
Fullterm baby 1-10 11-20 21-30 31-40 41-50 51-60 61-70 71-80 81-85
No. Cases
Av. Wt.
2
2.3
9 21 37 38 19 17 12
1.4 8.5
4
2
13.1 15.9 15.5 16.7 20.8 17.7 17.5
Min. Wt. Max. Wt. 2.0 0.8 1.0 7.0 7.0 9.0 7.0 9.0 14.0 15.0
2.6 2.0 14.5 25.0 29.0 25.0 30.0 51.0 22.0 20.0
II 7 IN
FIG. 1. Cut section of prostate shows nodules of various sizes, some bulging from cut surface. Nodule in upper periphery shows cystic change.
211
among the cells in the nodules. Such stromal nodules were occasionally encountered in close relation to a duct. Epithelium incorporating nodule: The histological features were the same as described under pure stromal nodules. In addition, it was observed that some stromal nodules showed at their periphery some compressed ducts with narrow lumina (fig. 3). These encircling ducts showed hyperplasia of their lining epithelium toward the nodule. In some cases this type of nodule was seen close to the pure stromal nodule. Stromal nodule with few epithelial structures: In these nodules well formed young acini were seen. However, the stroma was composed of similar cells as seen in pure stromal nodule. Mixed nodules. These were the most common type of nodules seen in cases of nodular hyperplasia. The nodule was composed of proliferating acini, muscle and fibrous tissue of varying proportion (fig. 4). The acini within the nodule were lined invariably by a single layer of tall columnar cells, which at places were hyperplastic and formed long branching peninsular processes. The epithelial cells had generally an amphophilic to eosinophilic granular cytoplasm, the nucleus being placed basally. Some cells showed secretion vacuoles in the cytoplasm. The luminal border of these cells were distinctly seen in most. At places the cell margin was adherent to the luminal secretion. The general epithelial character appeared similar to the epithelium in young prostates. Glandular nodules. This type of nodule presented a predominant proliferation of glandular elements with little stroma (fig. 5). The secretory
FIG. 2. Pure stromal nodule of loose texture and pale staining, compressing surrounding normal prostatic stroma. H & E, reduced from x48.
Gieson's elastic stain, it was demonstrated that the nodule was devoid of elastic fibers, whereas 'the surrounding tissue was quite rich in the same. Besides the loosely lying spindle cells the nodules entrapped young vascular channels, thick walled sinusoidal spaces, which at tiµies was difficult to distinguish from atrophic small ducts embedded within the nodule. Mitotic figures were not seen
FIG. 3. Pure stromal nodule surrounded by ducts shows hyperplasia of lining and outpouching of wall toward nodule. H & E, reduced from x48.
212
PRADHAN AND CHANDRA
nodule. The general glandular pattern in daughter nodules was similar to that seen in the mother nodules. Daughter nodule formation was commonly seen in cases when changes of nodular hyperplasia were marked. Leiomyomatous nodules. This type of nodule was characterized by proliferating mature smooth muscle bundles interspersed with scanty fibroconnective tissue within the nodule producing signs of compression of the surrounding tissue. In prostates in which nodular hyperplasia was marked a small amount of uninvolved compressed prostatic tissue was seen at the periphery, giving a vivid contrast to the state of glands in hyperplastic nodules. FIG. 4. Mixed nodule contains proliferating glandular, muscular and fibrous elements of varying proportion. H & E, reduced from x 48.
FIG. 5. Glandular nodule composed of mainly glandular tissue. At right upper comer, duct is seen to be compressed by expanding nodule. H & E, reduced from x48.
activity of the epithelium of mixed and glandular nodule was mild. The lumen contained no secretion in most acini or little secretion in some. Small corpora amylacea were seen occasionally. The number and size of corpora amylacea were appreciably less in hyperplastic nodules as compared to the surrounding uninvolved prostatic tissue.. Cystic change in mixed or glandular nodules was seen frequently. In such situations the epithelium was low columnar and single layered. Sometimes the cystic change was marked, giving a multilocular appearance. The general appearance was almost similar to cystic change occurring in simple atrophy of peripheral glands from which it was at times difficult to distinguish. Hyperplastic nodules showing such cystic change were evidently situated toward the peripheral portions, whereas the young and glandular nodules were located in the central portion of the prostate. Another feature of the mixed and glandular nodules was the formation of daughter nodules which were seen as a small area within a hyperplastic nodule, bringing about a centripetal compression of the remainder of the tissues of the mother
DISCUSSION
The problem of the earliest age at which nodular hyperplasia occurs is difficult to solve. In our study the earliest occurrence of microscopic nodular hyperplasia was seen in a prostate from a 35-yearold subject. The presence of any nodule as previously described was considered positive evidence of nodular hyperplasia. The incidence of nodular hyperplasia based on autopsy studies differ widely from the incidence based on clinical observations. An autopsy study is more objective and includes even the earliest stage of the lesion, which could not have produced any symptom to draw clinical attention. There is also a divergence in the incidence in different age groups, even when the studies are conducted on the analysis of autopsy material. From a review by Moore it is apparent that this variation is caused by the different methods and criteria for study.' Moore mentioned that benign hypertrophy of the prostate occurs with increasing frequency in patients more than 40 years old. He found that the age incidence of patients with sufficient obstruction to require surgical relief showed a maximal incidence in the seventh decade. He, by step-section technique, reported an incidence of 30 per cent in the fifth decade, 37 per cent in the sixth decade, 70 per cent in the seventh decade and 80 per cent after 80 years. No patient in his series less than 40 years old had evidence of nodular hyperplasia. The incidence of the lesion in different age groups in our study is shown in table 2. There have been many excellent studies on the morphogenesis of nodular hyperplasia. •- 5 Although most investigators believe that the lesion in benign prostatic enlargement is essentially a hyperplasia, there still exists some difference of opinion in the 1 Moore, R. A.: Benign hypertrophy of the prostate: a morphological study. J. Urol., 50: 680, 1943. 2 LeDuc, I. E.: The anatomy of the prostate and the pathology of early benign hypertrophy. J. Urol., 42: 1217, 1939. 'Tandler, J. and Zuckerkandl, 0.: Cited by Moore.' • Deming, C. L. and Neumann, C.: Early phases of prostatic hyperplasia .. Surg., Gynec. & Obst., 68: 155, 1939. 5 Franks, L. M.: Benign nodular hyperplasia of prostate; a review. Ann. Roy. Coll. Surg. Engl., 14: 92, 1954.
MORPHOGENESIS OF NODULAR HYPERPLASIA-PROSTATE TABLE
2. Incidence of nodular hyperplasia according to
age groups Age Groups (yrs.)
No. Cases
Nodular Hyperplasia No.(%)
31-40 41-50 51-60 61-70 71-80 81-85
38 19 17 12 4 2
7 (18) 6 (31) 9 (53) 7 (58) 3 (75) 2(100)
matter of the evolution of nodules. The results of the present study denote that the sequence of events of nodular hyperplasia may be explained in a way that the earliest detectable lesion probably begins as an early stromal nodule, occurring most commonly in the region adjacent to the urethra or in a periductal or periacinar situation. Such nodules are devoid of elastic fibers but take a positive stain for collagen. These nodules perhaps induce the encircling ducts to proliferate and to invade the solid nodule (epithelium incorporating nodule). The evidence in favor of this suggestion is that the encircling duct shows hyperplasia and outpouching of its wall toward the nodule (fig. 3). This feature may be interpreted as a process of budding of the ductal wall so that the epithelium penetrates the stromal nodule. This type of nodule has been designated as stromal nodule with epithelial structures. The evidence that this nodule arises from a pure stromal nodule is substantiated by the fact that the stroma of such a nodule possesses similar cellular characteristics as seen in pure stromal nodules containing in addition few epithelial elements. It further can be stated that in certain situations a pure stromal nodule and epithelium incorporated nodule were seen side by side, the former being closer to the urethra. This fact may help explain that the epithelium incorporated
213
nodule represents an older stromal nodule which has been pushed away from the urethra. With passing of time the stroma of the epithelium incorporated nodule probably proliferates and differentiates to form fibrous tissue and smooth muscle bundles within the nodule. While these changes are occurring in the stroma the epithelial structures also simultaneously proliferate. Now a pure stromal nodule is transformed into a mixed nodule containing proliferating fibrous, muscular and glandular tissue. When the epithelial elements grow more rapidly the nodule shows glandular predominance. This type of nodule has been designated a glandular nodule. The leiomyomatous nodule may be interpreted as an early nodule pursuing a one-side differentiation to muscular elements. The occurrence of daughter nodules and cystic change in a mixed or glandular nodule is thought to be a secondary change. Once the nodule becomes older it is pushed to the periphery. The resistance offered by the surrounding thin normal prostatic tissue is relatively less to the peripherally situated nodules, hence the cystic change. SUMMARY
Step-section study was done on 161 prostates from medicolegal autopsies. Nodular hyperplasia occurred in 35-year-old subjects but increased in frequency with advancing age. Nodular hyperplasia originates as an early stromal nodule usually by the side of urethra. This nodule perhaps stimulates the duct in its close vicinity to proliferate and to bud into the solid nodule. Thereafter, stromal and epithelial elements proliferate to form either a glandular or a mixed nodule. A leiomyomatous nodule has been interpreted as a unilateral differentiation and maturation of stromal nodule to smooth muscle.
Vol. 113, February Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1975 by The Williams & Wilkins Co.
MORPHOGENESIS OF NODULAR HYPERPLASIA-PROSTATE B. K. PRADHAN
AND
K. CHANDRA*
From the Department of Pathology, Maulana Azad Medical College and Irwin & G. B. Pant Hospitals, New Delhi, India
The etiology and morphogenesis of prostatic nodular hyperplasia, a common disease of elderly men, have been subjects of controversy for decades. Many theories have been proposed to explain the morphological patterns in the evolution of nodular hyperplasia. However, there still exists much speculation as to the relationship among the pure fibrous nodules, the pure glandular nodules and the mixed varieties. We have studied the incidence and morphological evolution of nodular hyperplasia by the stepsection technique, using material collected from the apparently asymptomatic population as represented in the medicolegal deaths autopsied. MATERIAL AND METHODS
Prostates were removed from 161 autopsy cases in 1 piece with the bladder and rectum. The complete prostate was then dissected and separated from the surrounding tissue. To facilitate deeper penetration of the preservative 1 or 2 cuts were made (depending on the size of the prostate) in transverse direction to the long axis of the gland. The prostate was preserved in 10 per cent buffered formalin for 24 to 48 hours, after which a detailed gross examination was done and sections were made. A rough outline of the complete gland was traced on paper to record an impression of its size, site of nodularity and asymmetry. The gland was then divided transversely into sections each 0.4 cm. apart. The sections were numbered starting from the superior end and proceeding toward the inferior end, each section representing a transverse section of the complete gland. After the tissues were embedded, the paraffin blocks, thus prepared, were cut from the superior aspect of each so that the sections from subsequent blocks were separated from each other roughly by 0.4 cm. All sections were stained with hematoxylin and eosin. Special stains for collagen, smooth muscle and elastic tissue were prepared when indicated. OBSERVATION
The age of patients from whom the prostates were taken ranged from newborn to 85 years. The cases were grouped in decades and the range of weights were noted (table 1). The prostate having maximum weight of 51 gm. was from a 70-year-old subject. Accepted for publication May 31, 1974. * Requests for reprints: Department of Pathology, Maulana Azad Medical College, New Delhi-1, India. 210
A naked eye examination of prostates in nodular hyperplasia revealed mild to moderate enlarge- · ment of the gland. Nodularity on the external surface was usually located laterally or anterolaterally and was noticed in 9 of 54 prostates from patients more than 40 years old (16.5 per cent). The cut surface of the prostates in nodular hyperplasia revealed nodules varying in size from 0.2 to 1.0 cm. in greatest dimension. They were well circumscribed, rounded areas in sharp contrast to the uniform, gray, homogeneous, glistening and firm normal prostatic tissue. Some nodules had a honey-combed appearance. Nodules on cut surface were seen in 20 of 54 prostates from patients more than 40 years old. The numerous nodules of varying size on cut surface produced compression and distortion of the urethra in several prostates (fig. 1). Microscopically a nodule was characterized by localized' proliferation of fibrous tissue, muscle tissue, glandular elements or their combination, with evidence of centrifugal expansion within the nodule producing obvious compression of the surrounding stroma or epithelial elements. Several types of nodules were recognized. Early nodule. An early nodule was recognized as a stromal focus of pale stained tissue, which in most cases was well circumscribed. In a few early nodules the nodular tissue at the periphery appeared to be merging into the surrounding stroma, thereby making the outline poorly defined. Most early nodules were close to or at some distance from the urethra. Some were in the middle zone of the prostate in close relation to the ducts and an occasional one was in the outer zone. A few stromal nodules were close to the prostatic utricle. Several types of early nodules were recognized. Pure stromal nodule: Stromal nodules were clearly distinguishable from the surrounding tissue by their loose texture and pale staining (fig. 2). They were composed of spindle cells with a round to oval nucleus, the chromatin of which was distributed evenly, giving a light staining reaction. The cytoplasm was lightly eosinophilic. The intercellular space was adequate and fibrillar in appearance owing to cytoplasmic processes extending from contiguous cells. The cytoplasm of the cells within the nodules took a positive stain for collagen. In contrast to this, the surrounding normal prostatic tissue was composed of spindle cells with elongated nuclei and tapering ends. The nuclei were densely chromatic and the cytoplasm was deeply eosinophilic. The intercellular substance contained an adequate amount of collagen. By van
MORPHOGENESIS OF NODULAR HYPERPLASIA-PROSTATE TABLE
1. Weight of prostate in grams and number of
cases according to age groups
Groups (yrs.)
Age
Fullterm baby 1-10 11-20 21-30 31-40 41-50 51-60 61-70 71-80 81-85
No. Cases
Av. Wt.
2
2.3
9 21 37 38 19 17 12
1.4 8.5
4
2
13.1 15.9 15.5 16.7 20.8 17.7 17.5
Min. Wt. Max. Wt. 2.0 0.8 1.0 7.0 7.0 9.0 7.0 9.0 14.0 15.0
2.6 2.0 14.5 25.0 29.0 25.0 30.0 51.0 22.0 20.0
II 7 IN
FIG. 1. Cut section of prostate shows nodules of various sizes, some bulging from cut surface. Nodule in upper periphery shows cystic change.
211
among the cells in the nodules. Such stromal nodules were occasionally encountered in close relation to a duct. Epithelium incorporating nodule: The histological features were the same as described under pure stromal nodules. In addition, it was observed that some stromal nodules showed at their periphery some compressed ducts with narrow lumina (fig. 3). These encircling ducts showed hyperplasia of their lining epithelium toward the nodule. In some cases this type of nodule was seen close to the pure stromal nodule. Stromal nodule with few epithelial structures: In these nodules well formed young acini were seen. However, the stroma was composed of similar cells as seen in pure stromal nodule. Mixed nodules. These were the most common type of nodules seen in cases of nodular hyperplasia. The nodule was composed of proliferating acini, muscle and fibrous tissue of varying proportion (fig. 4). The acini within the nodule were lined invariably by a single layer of tall columnar cells, which at places were hyperplastic and formed long branching peninsular processes. The epithelial cells had generally an amphophilic to eosinophilic granular cytoplasm, the nucleus being placed basally. Some cells showed secretion vacuoles in the cytoplasm. The luminal border of these cells were distinctly seen in most. At places the cell margin was adherent to the luminal secretion. The general epithelial character appeared similar to the epithelium in young prostates. Glandular nodules. This type of nodule presented a predominant proliferation of glandular elements with little stroma (fig. 5). The secretory
FIG. 2. Pure stromal nodule of loose texture and pale staining, compressing surrounding normal prostatic stroma. H & E, reduced from x48.
Gieson's elastic stain, it was demonstrated that the nodule was devoid of elastic fibers, whereas 'the surrounding tissue was quite rich in the same. Besides the loosely lying spindle cells the nodules entrapped young vascular channels, thick walled sinusoidal spaces, which at tiµies was difficult to distinguish from atrophic small ducts embedded within the nodule. Mitotic figures were not seen
FIG. 3. Pure stromal nodule surrounded by ducts shows hyperplasia of lining and outpouching of wall toward nodule. H & E, reduced from x48.
212
PRADHAN AND CHANDRA
nodule. The general glandular pattern in daughter nodules was similar to that seen in the mother nodules. Daughter nodule formation was commonly seen in cases when changes of nodular hyperplasia were marked. Leiomyomatous nodules. This type of nodule was characterized by proliferating mature smooth muscle bundles interspersed with scanty fibroconnective tissue within the nodule producing signs of compression of the surrounding tissue. In prostates in which nodular hyperplasia was marked a small amount of uninvolved compressed prostatic tissue was seen at the periphery, giving a vivid contrast to the state of glands in hyperplastic nodules. FIG. 4. Mixed nodule contains proliferating glandular, muscular and fibrous elements of varying proportion. H & E, reduced from x 48.
FIG. 5. Glandular nodule composed of mainly glandular tissue. At right upper comer, duct is seen to be compressed by expanding nodule. H & E, reduced from x48.
activity of the epithelium of mixed and glandular nodule was mild. The lumen contained no secretion in most acini or little secretion in some. Small corpora amylacea were seen occasionally. The number and size of corpora amylacea were appreciably less in hyperplastic nodules as compared to the surrounding uninvolved prostatic tissue.. Cystic change in mixed or glandular nodules was seen frequently. In such situations the epithelium was low columnar and single layered. Sometimes the cystic change was marked, giving a multilocular appearance. The general appearance was almost similar to cystic change occurring in simple atrophy of peripheral glands from which it was at times difficult to distinguish. Hyperplastic nodules showing such cystic change were evidently situated toward the peripheral portions, whereas the young and glandular nodules were located in the central portion of the prostate. Another feature of the mixed and glandular nodules was the formation of daughter nodules which were seen as a small area within a hyperplastic nodule, bringing about a centripetal compression of the remainder of the tissues of the mother
DISCUSSION
The problem of the earliest age at which nodular hyperplasia occurs is difficult to solve. In our study the earliest occurrence of microscopic nodular hyperplasia was seen in a prostate from a 35-yearold subject. The presence of any nodule as previously described was considered positive evidence of nodular hyperplasia. The incidence of nodular hyperplasia based on autopsy studies differ widely from the incidence based on clinical observations. An autopsy study is more objective and includes even the earliest stage of the lesion, which could not have produced any symptom to draw clinical attention. There is also a divergence in the incidence in different age groups, even when the studies are conducted on the analysis of autopsy material. From a review by Moore it is apparent that this variation is caused by the different methods and criteria for study.' Moore mentioned that benign hypertrophy of the prostate occurs with increasing frequency in patients more than 40 years old. He found that the age incidence of patients with sufficient obstruction to require surgical relief showed a maximal incidence in the seventh decade. He, by step-section technique, reported an incidence of 30 per cent in the fifth decade, 37 per cent in the sixth decade, 70 per cent in the seventh decade and 80 per cent after 80 years. No patient in his series less than 40 years old had evidence of nodular hyperplasia. The incidence of the lesion in different age groups in our study is shown in table 2. There have been many excellent studies on the morphogenesis of nodular hyperplasia. •- 5 Although most investigators believe that the lesion in benign prostatic enlargement is essentially a hyperplasia, there still exists some difference of opinion in the 1 Moore, R. A.: Benign hypertrophy of the prostate: a morphological study. J. Urol., 50: 680, 1943. 2 LeDuc, I. E.: The anatomy of the prostate and the pathology of early benign hypertrophy. J. Urol., 42: 1217, 1939. 'Tandler, J. and Zuckerkandl, 0.: Cited by Moore.' • Deming, C. L. and Neumann, C.: Early phases of prostatic hyperplasia .. Surg., Gynec. & Obst., 68: 155, 1939. 5 Franks, L. M.: Benign nodular hyperplasia of prostate; a review. Ann. Roy. Coll. Surg. Engl., 14: 92, 1954.
MORPHOGENESIS OF NODULAR HYPERPLASIA-PROSTATE TABLE
2. Incidence of nodular hyperplasia according to
age groups Age Groups (yrs.)
No. Cases
Nodular Hyperplasia No.(%)
31-40 41-50 51-60 61-70 71-80 81-85
38 19 17 12 4 2
7 (18) 6 (31) 9 (53) 7 (58) 3 (75) 2(100)
matter of the evolution of nodules. The results of the present study denote that the sequence of events of nodular hyperplasia may be explained in a way that the earliest detectable lesion probably begins as an early stromal nodule, occurring most commonly in the region adjacent to the urethra or in a periductal or periacinar situation. Such nodules are devoid of elastic fibers but take a positive stain for collagen. These nodules perhaps induce the encircling ducts to proliferate and to invade the solid nodule (epithelium incorporating nodule). The evidence in favor of this suggestion is that the encircling duct shows hyperplasia and outpouching of its wall toward the nodule (fig. 3). This feature may be interpreted as a process of budding of the ductal wall so that the epithelium penetrates the stromal nodule. This type of nodule has been designated as stromal nodule with epithelial structures. The evidence that this nodule arises from a pure stromal nodule is substantiated by the fact that the stroma of such a nodule possesses similar cellular characteristics as seen in pure stromal nodules containing in addition few epithelial elements. It further can be stated that in certain situations a pure stromal nodule and epithelium incorporated nodule were seen side by side, the former being closer to the urethra. This fact may help explain that the epithelium incorporated
213
nodule represents an older stromal nodule which has been pushed away from the urethra. With passing of time the stroma of the epithelium incorporated nodule probably proliferates and differentiates to form fibrous tissue and smooth muscle bundles within the nodule. While these changes are occurring in the stroma the epithelial structures also simultaneously proliferate. Now a pure stromal nodule is transformed into a mixed nodule containing proliferating fibrous, muscular and glandular tissue. When the epithelial elements grow more rapidly the nodule shows glandular predominance. This type of nodule has been designated a glandular nodule. The leiomyomatous nodule may be interpreted as an early nodule pursuing a one-side differentiation to muscular elements. The occurrence of daughter nodules and cystic change in a mixed or glandular nodule is thought to be a secondary change. Once the nodule becomes older it is pushed to the periphery. The resistance offered by the surrounding thin normal prostatic tissue is relatively less to the peripherally situated nodules, hence the cystic change. SUMMARY
Step-section study was done on 161 prostates from medicolegal autopsies. Nodular hyperplasia occurred in 35-year-old subjects but increased in frequency with advancing age. Nodular hyperplasia originates as an early stromal nodule usually by the side of urethra. This nodule perhaps stimulates the duct in its close vicinity to proliferate and to bud into the solid nodule. Thereafter, stromal and epithelial elements proliferate to form either a glandular or a mixed nodule. A leiomyomatous nodule has been interpreted as a unilateral differentiation and maturation of stromal nodule to smooth muscle.
