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Perineural Glands in Normal and Hyperplastic Prostates
0022-5347/80/1235-0686$02.00/0 Vol.123,May
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1980 by The Williams & Wilkins Co.
PERINEURAL GLANDS IN NORMAL AND HYPERPLASTIC PROSTATES PER HENRIK BECHER CARSTENS From the Department of Pathology, University of Louisville School of Medicine, Louisville, Kentucky
ABSTRACT
Serial sections from 1 block of either a normal or hyperplastic prostate demonstrated at least 2 foci of perineural invasion in 7 of 8 consecutive autopsies. In addition to the perineural invasion a close relationship was found among nerves, glandular epithelium and vascular structures in all 8 autopsies. Although there are differences between the epithelium in perineural invasion in carcinoma and in normal or hyperplastic prostates perineural invasion can no longer be regarded as unequivocal evidence of malignancy. Perineural invasion, that is the presence of epithelial cells within the perineurium, is regarded by many as evidence of malignancy. Especially when the histologic grade is low or the material is limited, as in a needle biopsy, perineural invasion often becomes the decisive factor in making a diagnosis of malignancy. Perineural invasion occurs in cancers of the breast, cervix, pancreas and stomach and, especially, in the prostate. In the older literature the term perineural lymphatic invasion frequently was used. 1• 2 However, light and electron microscopy has failed to demonstrate evidence oflymphatic channels in the perineurium. 3 Recently, doubt has been raised whether perineural invasion represents an unequivocal indication of malignancy in the breast. Several investigators have demonstrated perineural invasion in benign breast lesions.4 ' 5 This study was done to verify personal observations of perineural invasion in cases of normal and nodular prostatic hyperplasia (benign prostatic hyperplasia).
apparently stratified epithelium, consisting of an inner layer of columnar cells surrounded by flattened cells with their long axis at right angles to the axis of the cells in the inner layer (fig. 1, A). The cells were well differentiated without cytologic atypia. Serial sections failed to demonstrate any foci of prostatic carcinoma, nor was vascular or stromal invasion noted in any of the 8 blocks. In addition to the perineural invasion described previously, a close relationship between nerves and glandular epithelium also was found in all of the blocks, sometimes including small vascular structures (fig. 2, B). In these instances a small nerve was noted close to 1 or several glandular structures without intervening stroma. The glandular structure usually was larger than the nerve and had a close relationship to the nerve for a short segment of its entire circumference. Therefore, this did not simulate the perineural invasion, in which the glandular epithelium is maintained within the perineurium. DISCUSSION
MATERIALS
From 46 to 121 serial sections of prostate were cut at 5 µ,m. on 1 block each from 8 consecutive autopsies without malignancies. On gross and microscopic examination 3 prostates were normal and 5 contained nodular prostatic hyperplasia. The patient age, prostatic morphology, cause of death and number of perineural invasions are shown in the table. The sections were stained with hematoxylin and eosin. One section from each autopsy demonstrating perineural invasion was destained and restained by Bodian's method for nerve fibers and nerve endings. RESULTS
All but 1 of the 8 prostates had at least 2 different foci of perineural invasion. The Bodian stain reconfirmed that the structure identified in the hematoxylin and eosin-stained section was, indeed, a nerve. Most of the blocks included a portion of the posterior lobe and the capsule. There was no special distribution of the perineural invasion within the blocks. The foci of perineural invasion were continuous with parenchymal glandular structures. The glandular invasion most ofter, occupied only part of the circumference of the nerve, and a nerve was never surrounded completely by glandular epithelium (figs. 1 and 2, A). The glandular epithelium was never noted to be lying in a space lined by flattened endothelial-like cells. The glandular structures consisted of small, regular lumina often lined by an Accepted for publication July 20, 1979.
686
The first description of perineural invasion is attributed to Ernst in 1905 in a case of chondrosarcoma. 6 Since that report this phenomenon has been noted in cancers of many organs. Perineural invasion has been characterized as the most reliable pathologic evidence for the diagnosis of carcinoma of the prostate. 7 Furthermore, Waisman and Mott stated that benign perineural invasion has not yet been reported in the prostate gland. 8 In this study 8 consecutive autopsies from which prostatic tissue that did not have any foci of malignancy were studied by serial section for perineural invasion. The prostates were either normal or hyperplastic and 7 showed multiple foci of perineural invasion. The glandular epithelium studied herein differed from the epithelium found in perineural invasion in prostatic cancer in several ways. First, the epithelium was stratified with 2 layers of cells. The inner layer of columnar cells was surrounded by flattened myoepithelial-like cells. In prostatic carcinoma the glandular epithelium usually consists of only 1 layer of columnar or cuboidal cells. In addition, no cytologic atypia was present in the glandular epithelium and the glandular epithelium only occupied a portion of the circumference of the nerve. Although this can be the case in perineural invasion in prostatic carcinoma it is quite common to see some foci of complete encirclement of the nerve. The glandular epithelium was never noted to lie in an endothelial-lined space, which is consistent with prior light and electron microscopic studies, indicating that the perineural lymphatic space is a highly questionable entity. 3 The explanation for finding growth of glandular epithelium along nerves may, in the case of prostatic hyperplasia or carci-
PERINEURAL GLANDS IN NORMAL AND HYPERPLASTIC PROSTATES
noma, be that the perineural space offers a growth plane of less resistance than the surrounding stroma. However, the finding of perineural invasion in the normal prostate cannot be explained in this way. It is noteworthy that in this study a close Review of autopsies Pt. Age (yrs.)
Morphology
Cause of Death
No. Perineural Inv9 .-
~ions 29 48 53 37 54 63 73 74
Normal Normal Normal Nodular hyperplasia Nodular hyperplasia Nodular hyperplasia Nodular hyperplasia Nodular hyperplasia
Sepsis Pneumonia Pneumonia Hepatitis Peritonitis Pneumonia Cerebral hemorrhage Pneumonia
3 4 5 2 2 3 2 0
687
relationship among nerves, glandular epithelium and, sometimes, blood vessels was found in all 8 prostates without the glandular epithelium being contained completely within the perineurium as in the classic perineural invasion. It is tempting to suggest that the close relationship that exists among nerves, glandular epithelium and vascular structures under normal conditions is accentuated under certain circumstances, neoplastic as well as non-neoplastic, to produce a picture of perineural invasion. It is highly unlikely that all of the perineural invasions in these consecutive normal or hyperplastic prostates represent invasion from small foci of carcinoma in areas of the prostate not sampled. This study clearly demonstrates that perineural invasion does occur in normal prostates and in prostates with nodular hyperplasia. Although there are some differences between the appearance of the glandular epithelium in cases of carcinoma and in the normal or hyperplastic prostate, perineural invasion clearly cannot be used as unequivocal evidence for malignancy.
FIG. 1. Perineural invasion in normal prostates. Epithelium appears stratified. H & E, reduced from X160
;j
FIG. 2. A, perineural invasion in hyperplastic prostate. Epithelium appears stratified and lying in dilated perineural space without endothelial lining. H & E, reduced from X416. B, close relationship among glands, nerve and vascular structure in hyperplastic prostate. H & E, reduced from X160.
688
CARSTENS
Cytologic atypia, and vascular and stromal invasion appear to be much more reliable parameters of malignancy. Technical assistance was provided by Mrs. June Byrum and Mr. Wally L. Past. REFERENCES 1. Moore, R. A.: The morphology of small prostatic carcinoma. J.
Urol., 33: 224, 1935. 2. Warren, S., Harris, P. N. and Graves, R. C.: Osseous metastasis of carcinoma of the prostate: with special reference to perineural lymphatics. Arch. Path., 22: 139, 1936. 3. Rodin, A. A., Larson, D. L. and Roberts, D. K.: Nature of the perineural space invaded by prostatic carcinoma. Cancer, 20: 1772, 1967.
4. Gould, V. E., Rogers, D.R. and Sommers, S. C.: Epithelial-nerve intermingling in benign breast lesions. Arch. Path., 99: 596, 1975. 5. Taylor, H. B. and Norris, H. J.: Epithelial invasion of nerves in benign diseases of the breast. Cancer, 20: 2245, 1967. 6. Ernst, P.: Ueber das Wachstum und die Verbreitung bosartiger Geschwiilste, insbesondere des Krebses in den Lymphbahnen der Nerven; ein Beitrag zur Biologie des Krebses. Beitr. Path. Anat., suppl. 7, p. 29, 1905. 7. Mostofi, F. K. and Price, E. B., Jr.: Tumors of the male genital system. In: Atlas of Tumor Pathology.Washington, D. C.: Armed Forces Institute of Pathology, 2nd series, fasc. 8, p. 214, 1973. 8. Waisman, J. and Mott, L. J. M.: Pathology of neoplasms of the prostate gland. In: Genitourinary Cancer. Edited by D. G. Skinner and J.B. deKernion. Philadelphia: W. B. Saunders Co., p. 327, 1978.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1980 by The Williams & Wilkins Co.
PERINEURAL GLANDS IN NORMAL AND HYPERPLASTIC PROSTATES PER HENRIK BECHER CARSTENS From the Department of Pathology, University of Louisville School of Medicine, Louisville, Kentucky
ABSTRACT
Serial sections from 1 block of either a normal or hyperplastic prostate demonstrated at least 2 foci of perineural invasion in 7 of 8 consecutive autopsies. In addition to the perineural invasion a close relationship was found among nerves, glandular epithelium and vascular structures in all 8 autopsies. Although there are differences between the epithelium in perineural invasion in carcinoma and in normal or hyperplastic prostates perineural invasion can no longer be regarded as unequivocal evidence of malignancy. Perineural invasion, that is the presence of epithelial cells within the perineurium, is regarded by many as evidence of malignancy. Especially when the histologic grade is low or the material is limited, as in a needle biopsy, perineural invasion often becomes the decisive factor in making a diagnosis of malignancy. Perineural invasion occurs in cancers of the breast, cervix, pancreas and stomach and, especially, in the prostate. In the older literature the term perineural lymphatic invasion frequently was used. 1• 2 However, light and electron microscopy has failed to demonstrate evidence oflymphatic channels in the perineurium. 3 Recently, doubt has been raised whether perineural invasion represents an unequivocal indication of malignancy in the breast. Several investigators have demonstrated perineural invasion in benign breast lesions.4 ' 5 This study was done to verify personal observations of perineural invasion in cases of normal and nodular prostatic hyperplasia (benign prostatic hyperplasia).
apparently stratified epithelium, consisting of an inner layer of columnar cells surrounded by flattened cells with their long axis at right angles to the axis of the cells in the inner layer (fig. 1, A). The cells were well differentiated without cytologic atypia. Serial sections failed to demonstrate any foci of prostatic carcinoma, nor was vascular or stromal invasion noted in any of the 8 blocks. In addition to the perineural invasion described previously, a close relationship between nerves and glandular epithelium also was found in all of the blocks, sometimes including small vascular structures (fig. 2, B). In these instances a small nerve was noted close to 1 or several glandular structures without intervening stroma. The glandular structure usually was larger than the nerve and had a close relationship to the nerve for a short segment of its entire circumference. Therefore, this did not simulate the perineural invasion, in which the glandular epithelium is maintained within the perineurium. DISCUSSION
MATERIALS
From 46 to 121 serial sections of prostate were cut at 5 µ,m. on 1 block each from 8 consecutive autopsies without malignancies. On gross and microscopic examination 3 prostates were normal and 5 contained nodular prostatic hyperplasia. The patient age, prostatic morphology, cause of death and number of perineural invasions are shown in the table. The sections were stained with hematoxylin and eosin. One section from each autopsy demonstrating perineural invasion was destained and restained by Bodian's method for nerve fibers and nerve endings. RESULTS
All but 1 of the 8 prostates had at least 2 different foci of perineural invasion. The Bodian stain reconfirmed that the structure identified in the hematoxylin and eosin-stained section was, indeed, a nerve. Most of the blocks included a portion of the posterior lobe and the capsule. There was no special distribution of the perineural invasion within the blocks. The foci of perineural invasion were continuous with parenchymal glandular structures. The glandular invasion most ofter, occupied only part of the circumference of the nerve, and a nerve was never surrounded completely by glandular epithelium (figs. 1 and 2, A). The glandular epithelium was never noted to be lying in a space lined by flattened endothelial-like cells. The glandular structures consisted of small, regular lumina often lined by an Accepted for publication July 20, 1979.
686
The first description of perineural invasion is attributed to Ernst in 1905 in a case of chondrosarcoma. 6 Since that report this phenomenon has been noted in cancers of many organs. Perineural invasion has been characterized as the most reliable pathologic evidence for the diagnosis of carcinoma of the prostate. 7 Furthermore, Waisman and Mott stated that benign perineural invasion has not yet been reported in the prostate gland. 8 In this study 8 consecutive autopsies from which prostatic tissue that did not have any foci of malignancy were studied by serial section for perineural invasion. The prostates were either normal or hyperplastic and 7 showed multiple foci of perineural invasion. The glandular epithelium studied herein differed from the epithelium found in perineural invasion in prostatic cancer in several ways. First, the epithelium was stratified with 2 layers of cells. The inner layer of columnar cells was surrounded by flattened myoepithelial-like cells. In prostatic carcinoma the glandular epithelium usually consists of only 1 layer of columnar or cuboidal cells. In addition, no cytologic atypia was present in the glandular epithelium and the glandular epithelium only occupied a portion of the circumference of the nerve. Although this can be the case in perineural invasion in prostatic carcinoma it is quite common to see some foci of complete encirclement of the nerve. The glandular epithelium was never noted to lie in an endothelial-lined space, which is consistent with prior light and electron microscopic studies, indicating that the perineural lymphatic space is a highly questionable entity. 3 The explanation for finding growth of glandular epithelium along nerves may, in the case of prostatic hyperplasia or carci-
PERINEURAL GLANDS IN NORMAL AND HYPERPLASTIC PROSTATES
noma, be that the perineural space offers a growth plane of less resistance than the surrounding stroma. However, the finding of perineural invasion in the normal prostate cannot be explained in this way. It is noteworthy that in this study a close Review of autopsies Pt. Age (yrs.)
Morphology
Cause of Death
No. Perineural Inv9 .-
~ions 29 48 53 37 54 63 73 74
Normal Normal Normal Nodular hyperplasia Nodular hyperplasia Nodular hyperplasia Nodular hyperplasia Nodular hyperplasia
Sepsis Pneumonia Pneumonia Hepatitis Peritonitis Pneumonia Cerebral hemorrhage Pneumonia
3 4 5 2 2 3 2 0
687
relationship among nerves, glandular epithelium and, sometimes, blood vessels was found in all 8 prostates without the glandular epithelium being contained completely within the perineurium as in the classic perineural invasion. It is tempting to suggest that the close relationship that exists among nerves, glandular epithelium and vascular structures under normal conditions is accentuated under certain circumstances, neoplastic as well as non-neoplastic, to produce a picture of perineural invasion. It is highly unlikely that all of the perineural invasions in these consecutive normal or hyperplastic prostates represent invasion from small foci of carcinoma in areas of the prostate not sampled. This study clearly demonstrates that perineural invasion does occur in normal prostates and in prostates with nodular hyperplasia. Although there are some differences between the appearance of the glandular epithelium in cases of carcinoma and in the normal or hyperplastic prostate, perineural invasion clearly cannot be used as unequivocal evidence for malignancy.
FIG. 1. Perineural invasion in normal prostates. Epithelium appears stratified. H & E, reduced from X160
;j
FIG. 2. A, perineural invasion in hyperplastic prostate. Epithelium appears stratified and lying in dilated perineural space without endothelial lining. H & E, reduced from X416. B, close relationship among glands, nerve and vascular structure in hyperplastic prostate. H & E, reduced from X160.
688
CARSTENS
Cytologic atypia, and vascular and stromal invasion appear to be much more reliable parameters of malignancy. Technical assistance was provided by Mrs. June Byrum and Mr. Wally L. Past. REFERENCES 1. Moore, R. A.: The morphology of small prostatic carcinoma. J.
Urol., 33: 224, 1935. 2. Warren, S., Harris, P. N. and Graves, R. C.: Osseous metastasis of carcinoma of the prostate: with special reference to perineural lymphatics. Arch. Path., 22: 139, 1936. 3. Rodin, A. A., Larson, D. L. and Roberts, D. K.: Nature of the perineural space invaded by prostatic carcinoma. Cancer, 20: 1772, 1967.
4. Gould, V. E., Rogers, D.R. and Sommers, S. C.: Epithelial-nerve intermingling in benign breast lesions. Arch. Path., 99: 596, 1975. 5. Taylor, H. B. and Norris, H. J.: Epithelial invasion of nerves in benign diseases of the breast. Cancer, 20: 2245, 1967. 6. Ernst, P.: Ueber das Wachstum und die Verbreitung bosartiger Geschwiilste, insbesondere des Krebses in den Lymphbahnen der Nerven; ein Beitrag zur Biologie des Krebses. Beitr. Path. Anat., suppl. 7, p. 29, 1905. 7. Mostofi, F. K. and Price, E. B., Jr.: Tumors of the male genital system. In: Atlas of Tumor Pathology.Washington, D. C.: Armed Forces Institute of Pathology, 2nd series, fasc. 8, p. 214, 1973. 8. Waisman, J. and Mott, L. J. M.: Pathology of neoplasms of the prostate gland. In: Genitourinary Cancer. Edited by D. G. Skinner and J.B. deKernion. Philadelphia: W. B. Saunders Co., p. 327, 1978.