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Mechanisms of Calcification in Peyronie’s Disease
0022-534 7/82/1271-0052$02.00/0
Vol. 127, January
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1982 by The Williams & Wilkins Co.
MECHANISMS OF CALCIFICATION IN PEYRONIE'S DISEASE J. S. VANDE BERG, C. J. DEVINE, JR., C. E. HORTON, K. D. SOMERS, G. L. WRIGHT, JR., M. S. LEFFELL, D. M. DAWSON, S. H. GLEISCHMAN AND M. J. ROWE From the Veterans Administration Medical Center, San Diego, California, and the Departments of Urology, Plastic Surgery, Microbiology, Immunology and Biochemistry, Eastern Virginia Medical School and Medical Center Hospitals, Norfolk, Virginia
ABSTRACT
Scanning and transmission electron micrographs demonstrate a calcification process in the penile plaques of patients with Peyronie's disease. Osteoid formation originates from vascular lumina via osteoblast-like cells, which align the calcified plaque. These cells are surrounded gradually by calcified connective tissue. Collagen fibers demonstrate calcification and decreased periodicity. The occurrence of calcification in penile plaques from patients with Peyronie's disease has been reported in the literature on numerous occasions. 1- 6 Although relatively uncommon in the majority of plaque formations calcification generally occurs as an end point in this disorder. More importantly, calcification represents a phase in Peyronie's disease when the prevailing methods of chemical and radiation therapy have minimal effect. The alternative treatment at this stage has been an operation. In addition to providing a definitive ultrastructural description of the late stages of Peyronie's disease, we herein present morphological evidence of the manner in which dystrophic calcification occurs in penile plaques.
calcification could be followed into the septum between the corpora. With light microscopic examination all calcified plaques were located in the tunica albuginea. In most instances calcification appeared to originate from the vascular areas (figs. 1, A and 2, A), extending outwardly in a recurrent lamellar fashion through the connective tissue. Peripheral to the lamellar areas the connective tissue was dense and acellular. Random aggregates of calcification could be observed within both sites (figs. 3, B and 2, A). In all lamellar areas only 1 cell type was evident. Morpholog-
MATERIALS AND METHODS
Plaque and adjacent normal tissue from patients with Peyronie's disease, as well as control specimens from patients having scar and hypospadias repair, were obtained in the operating room and placed directly into cold (4C) buffered Karnovsky's fixative, pH 7.4. Each piece of tissue was further diced into small pieces (
Penile plaques were removed surgically from 20 patients who were diagnosed as having Peyronie's disease. Of these patients, 30 per cent exhibited plaques containing calcification. Clinical histories of these patients indicated that symptoms of Peyronie's disease had existed for 2 to 3 years. All calcified areas were observed primarily as single pieces rather than multiple fragments in the dorsal aspect of the penis. In 1 patient
FIG. 1. A, scanning electron micrograph of vascular lumen (L) surrounded by lamellar areas (arrows) of calcified connective tissue. Reduced from X650. B, enlarged magnification of calcified plaque surrounding vascular lumen. Note presence of osteoblast-like cells (Os) in calcified plaque (CP). Dense connective tissue (CT) occurs adjacent to calcified plaque. Reduced from Xl,050.
Accepted for publication April 24, 1981.
52
A, cross section of vascular lumen in area of pre-calcification, presence of cells (arrows) endothelial cells, which 1,n,v,uc,,L,a, featlir8S USUc(JU'Ldb Cells in Calcified from x8,000, (arrow) and decreased
this cell to resemble an osteoblast but, unlike an osteoblast, it cont&cined a nether electron dense and was deficient in mitochondria ar:_d -~'It'''-''"""~ rnticuiurn 3, B). Each cell DClS1,e13s,"d extensions drawn out a ,usu~,,,,., of dense ossification and 3, In a pfane cellular extensions ccn1Id be follovved passages within the cssified tissue 3, B), \JVithir~ the ossified vvere obse-:'.',.ved.
of 24 to 48 nm,
to 60 to 62 DJn. in
<:r,,o,•rnr"'·n
ossified 1~& trix
DISCUSS~ON
sections of tb.ese .0.re:1s N;")T,cr,rn,C' lamina B). This arrangement of concentric lamellae co:res cu,u,,co,IV resembled a haversian system of bone formation. In support cf this ntPT'n,-pj·;i,·rn,n additional interstitial. larr1eHae were D.oted, aDYt','Qar•nn and almost 10:ng1u1mmEu pattern ""'~n,u,.eu second acnor.,5
Ccicific::ition that has been individuals
have norma.l All individuals in our were believed to h.Rve no:rr.na1 se:rnrn concentrations cf these cl0_, ~Len.ts. While trauma has been """"''°"'"""' factor in the cause of disease histories do not corroborate these notions. An immunological factor also should be considered, since approximately 10 per cent of these patients may have other types of fibromatoses, such as Dupuytren's contracture and plantar fibromatosis. 3 We herein compare our ultrastructural data with dystrophic calcification in the scrotum, 8 lungs 7 and porcine xenograft valves. 6 The genernl pattern of metaplastic ossification in all tissues appeared similar but the latter reports lacked emphasis
54
VANDE BERG AND ASSOCIATES
Fm. 5. Diagrammatic presentation of suggested calcification process based on serial thick and thin sections. Pre-osteoblast cells (Pob) surrounding vascular lumen line up along calcified plaque. It is proposed that these cells become enclosed in gradual formation of calcified plaque. CP, calcified plaque. Os, osteoblast-like cell. E, elastic fiber.
Fm. 4. A, scanning electron micrograph of spongy-like bone (Sb) within vascular lumen, which occurs adjacent to calcified plaque. Note red blood cells (Rbc) appear immobilized within bone matrix. Reduced from Xll,900. B, polarizing light micrograph of unstained section of calcified plaque. Note haversian canals (arrows) surrounded by alternating anisotropic, isotropic lamellae. Reduced from Xl,600.
on the calcification process, malting any detailed comparison difficult. The report of Thandroyen and associates6 on dystrophic calcification in porcine xenograft valves preceded by degenerating collagen was in agreement with our previous study. 9 In this earlier report we noted that degeneration and/or reorganization of connective tissue also involved elastogenesis between collagen bundles. Serre and associates have suggested that advanced stages of connective tissue disease could initiate from collagen degeneration. 10 Our data support this notion and, additionally, suggest that collagen degeneration leading to calcification originates from regions of vascularity (figs. 1, 2, A and 3,A). Based on numerous thick and thin sections we have observed numerous pre-osteoblast-like cells in intermittent rings immediately peripheral to endothelial cells (figs. 1, B, 2, A and 3, A). Bordering these areas there is a depolymerization of collagen fibers, with a simultaneous appearance of increasing amounts of elastic fiber development. 9 Random aggregates of hydroxyapatite crystals (fig. 3, B) appear in the interstitial matrix and are deposited directly on collagen fibers (fig. 2). As calcification continues the pre-osteoblasts, which now resemble osteoblasts, become entirely enclosed in a dense osteoid plate (fig. 5). Other osteoblasts line up along the bone fragments and eventually become surrounded with subsequent calcification. As the os-
teoid plate grows the vascular lumina become occluded by a spongy matrix, retaining all cells in place (figs. 4, A and 5). As mentioned previously other studies illustrated dystrophic calcification occurring in soft tissues but no mention was made as to the origin or sequence of events in this process. 5-s We believe that these data strongly suggest that dystrophic calcification of penile plaques originates from vascular areas and support the notion that the pathogenesis of Peyronie's disease may result from an autoimmune stimulus antecedent to some form of vascular trauma. However, it should be cautioned that while these hypotheses are based on a morphological interpretation of numerous sections confirmation of these data will require verification by biochemical and cytochemical analyses.
REFERENCES 1. Eglitis, J. A.: Occurrence of bone tissue in the human penis. J. Urol., 70: 749, 1953. 2. Chesney, J.: Peyronie's disease. Brit. J. Urol., 47: 209, 1975. 3. Billig, R., Baker, R., Immergut, M. and Maxted, W.: Peyronie's disease. Urology, 6: 409, 1975. 4. Devine, C. J., Jr. and Horton, C. E.: Surgical treatment of Peyronie's disease with a dermal graft. J. Urol., 111: 44, 1974. 5. Smith, B. H.: Peyronie's disease. Amer. J. Clin. Path., 45: 670, 1966. 6. Thandroyen, F. T., Whitton, I. N., Pirie, D., Rogers, M. A. and Mitha, A. S.: Severe calcification of glutaraldehyde-preserved porcine xenografts in children. Amer. J. Cardiol., 45: 690, 1980. 7. Wang, N. and Steele, A. A.: Pulmonary calcification. Arch. Path. Lab. Med., 103: 252, 1979. 8. King, D. T., Brosman, S., Hirose, F. M. and Gillespie, L. M.: Idiopathic calcinosis of scrotum. Urology, 14: 92, 1979. 9. Vande Berg, J. S., Devine, C. J., Horton, C. E., Somers, K. D., Wright, G. L., Jr., Leffell, M. S., Dawson, D. M., Gleischman, S. H. and Rowe, M. J.: Peyronie's disease: an electron microscopic study. J. Urol., 126: 333, 1981. 10. Serre, H., Izarn, P., Simon, L., Sany, J., Baldet, P. and Privat, J. M.: Calcinose circonscrite idiopathique. Presse Med., 77: 1529, 1969.
Vol. 127, January
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1982 by The Williams & Wilkins Co.
MECHANISMS OF CALCIFICATION IN PEYRONIE'S DISEASE J. S. VANDE BERG, C. J. DEVINE, JR., C. E. HORTON, K. D. SOMERS, G. L. WRIGHT, JR., M. S. LEFFELL, D. M. DAWSON, S. H. GLEISCHMAN AND M. J. ROWE From the Veterans Administration Medical Center, San Diego, California, and the Departments of Urology, Plastic Surgery, Microbiology, Immunology and Biochemistry, Eastern Virginia Medical School and Medical Center Hospitals, Norfolk, Virginia
ABSTRACT
Scanning and transmission electron micrographs demonstrate a calcification process in the penile plaques of patients with Peyronie's disease. Osteoid formation originates from vascular lumina via osteoblast-like cells, which align the calcified plaque. These cells are surrounded gradually by calcified connective tissue. Collagen fibers demonstrate calcification and decreased periodicity. The occurrence of calcification in penile plaques from patients with Peyronie's disease has been reported in the literature on numerous occasions. 1- 6 Although relatively uncommon in the majority of plaque formations calcification generally occurs as an end point in this disorder. More importantly, calcification represents a phase in Peyronie's disease when the prevailing methods of chemical and radiation therapy have minimal effect. The alternative treatment at this stage has been an operation. In addition to providing a definitive ultrastructural description of the late stages of Peyronie's disease, we herein present morphological evidence of the manner in which dystrophic calcification occurs in penile plaques.
calcification could be followed into the septum between the corpora. With light microscopic examination all calcified plaques were located in the tunica albuginea. In most instances calcification appeared to originate from the vascular areas (figs. 1, A and 2, A), extending outwardly in a recurrent lamellar fashion through the connective tissue. Peripheral to the lamellar areas the connective tissue was dense and acellular. Random aggregates of calcification could be observed within both sites (figs. 3, B and 2, A). In all lamellar areas only 1 cell type was evident. Morpholog-
MATERIALS AND METHODS
Plaque and adjacent normal tissue from patients with Peyronie's disease, as well as control specimens from patients having scar and hypospadias repair, were obtained in the operating room and placed directly into cold (4C) buffered Karnovsky's fixative, pH 7.4. Each piece of tissue was further diced into small pieces (
Penile plaques were removed surgically from 20 patients who were diagnosed as having Peyronie's disease. Of these patients, 30 per cent exhibited plaques containing calcification. Clinical histories of these patients indicated that symptoms of Peyronie's disease had existed for 2 to 3 years. All calcified areas were observed primarily as single pieces rather than multiple fragments in the dorsal aspect of the penis. In 1 patient
FIG. 1. A, scanning electron micrograph of vascular lumen (L) surrounded by lamellar areas (arrows) of calcified connective tissue. Reduced from X650. B, enlarged magnification of calcified plaque surrounding vascular lumen. Note presence of osteoblast-like cells (Os) in calcified plaque (CP). Dense connective tissue (CT) occurs adjacent to calcified plaque. Reduced from Xl,050.
Accepted for publication April 24, 1981.
52
A, cross section of vascular lumen in area of pre-calcification, presence of cells (arrows) endothelial cells, which 1,n,v,uc,,L,a, featlir8S USUc(JU'Ldb Cells in Calcified from x8,000, (arrow) and decreased
this cell to resemble an osteoblast but, unlike an osteoblast, it cont&cined a nether electron dense and was deficient in mitochondria ar:_d -~'It'''-''"""~ rnticuiurn 3, B). Each cell DClS1,e13s,"d extensions drawn out a ,usu~,,,,., of dense ossification and 3, In a pfane cellular extensions ccn1Id be follovved passages within the cssified tissue 3, B), \JVithir~ the ossified vvere obse-:'.',.ved.
of 24 to 48 nm,
to 60 to 62 DJn. in
<:r,,o,•rnr"'·n
ossified 1~& trix
DISCUSS~ON
sections of tb.ese .0.re:1s N;")T,cr,rn,C' lamina B). This arrangement of concentric lamellae co:res cu,u,,co,IV resembled a haversian system of bone formation. In support cf this ntPT'n,-pj·;i,·rn,n additional interstitial. larr1eHae were D.oted, aDYt','Qar•nn and almost 10:ng1u1mmEu pattern ""'~n,u,.eu second acnor
Ccicific::ition that has been individuals
have norma.l All individuals in our were believed to h.Rve no:rr.na1 se:rnrn concentrations cf these cl0_, ~Len.ts. While trauma has been """"''°"'"""' factor in the cause of disease histories do not corroborate these notions. An immunological factor also should be considered, since approximately 10 per cent of these patients may have other types of fibromatoses, such as Dupuytren's contracture and plantar fibromatosis. 3 We herein compare our ultrastructural data with dystrophic calcification in the scrotum, 8 lungs 7 and porcine xenograft valves. 6 The genernl pattern of metaplastic ossification in all tissues appeared similar but the latter reports lacked emphasis
54
VANDE BERG AND ASSOCIATES
Fm. 5. Diagrammatic presentation of suggested calcification process based on serial thick and thin sections. Pre-osteoblast cells (Pob) surrounding vascular lumen line up along calcified plaque. It is proposed that these cells become enclosed in gradual formation of calcified plaque. CP, calcified plaque. Os, osteoblast-like cell. E, elastic fiber.
Fm. 4. A, scanning electron micrograph of spongy-like bone (Sb) within vascular lumen, which occurs adjacent to calcified plaque. Note red blood cells (Rbc) appear immobilized within bone matrix. Reduced from Xll,900. B, polarizing light micrograph of unstained section of calcified plaque. Note haversian canals (arrows) surrounded by alternating anisotropic, isotropic lamellae. Reduced from Xl,600.
on the calcification process, malting any detailed comparison difficult. The report of Thandroyen and associates6 on dystrophic calcification in porcine xenograft valves preceded by degenerating collagen was in agreement with our previous study. 9 In this earlier report we noted that degeneration and/or reorganization of connective tissue also involved elastogenesis between collagen bundles. Serre and associates have suggested that advanced stages of connective tissue disease could initiate from collagen degeneration. 10 Our data support this notion and, additionally, suggest that collagen degeneration leading to calcification originates from regions of vascularity (figs. 1, 2, A and 3,A). Based on numerous thick and thin sections we have observed numerous pre-osteoblast-like cells in intermittent rings immediately peripheral to endothelial cells (figs. 1, B, 2, A and 3, A). Bordering these areas there is a depolymerization of collagen fibers, with a simultaneous appearance of increasing amounts of elastic fiber development. 9 Random aggregates of hydroxyapatite crystals (fig. 3, B) appear in the interstitial matrix and are deposited directly on collagen fibers (fig. 2). As calcification continues the pre-osteoblasts, which now resemble osteoblasts, become entirely enclosed in a dense osteoid plate (fig. 5). Other osteoblasts line up along the bone fragments and eventually become surrounded with subsequent calcification. As the os-
teoid plate grows the vascular lumina become occluded by a spongy matrix, retaining all cells in place (figs. 4, A and 5). As mentioned previously other studies illustrated dystrophic calcification occurring in soft tissues but no mention was made as to the origin or sequence of events in this process. 5-s We believe that these data strongly suggest that dystrophic calcification of penile plaques originates from vascular areas and support the notion that the pathogenesis of Peyronie's disease may result from an autoimmune stimulus antecedent to some form of vascular trauma. However, it should be cautioned that while these hypotheses are based on a morphological interpretation of numerous sections confirmation of these data will require verification by biochemical and cytochemical analyses.
REFERENCES 1. Eglitis, J. A.: Occurrence of bone tissue in the human penis. J. Urol., 70: 749, 1953. 2. Chesney, J.: Peyronie's disease. Brit. J. Urol., 47: 209, 1975. 3. Billig, R., Baker, R., Immergut, M. and Maxted, W.: Peyronie's disease. Urology, 6: 409, 1975. 4. Devine, C. J., Jr. and Horton, C. E.: Surgical treatment of Peyronie's disease with a dermal graft. J. Urol., 111: 44, 1974. 5. Smith, B. H.: Peyronie's disease. Amer. J. Clin. Path., 45: 670, 1966. 6. Thandroyen, F. T., Whitton, I. N., Pirie, D., Rogers, M. A. and Mitha, A. S.: Severe calcification of glutaraldehyde-preserved porcine xenografts in children. Amer. J. Cardiol., 45: 690, 1980. 7. Wang, N. and Steele, A. A.: Pulmonary calcification. Arch. Path. Lab. Med., 103: 252, 1979. 8. King, D. T., Brosman, S., Hirose, F. M. and Gillespie, L. M.: Idiopathic calcinosis of scrotum. Urology, 14: 92, 1979. 9. Vande Berg, J. S., Devine, C. J., Horton, C. E., Somers, K. D., Wright, G. L., Jr., Leffell, M. S., Dawson, D. M., Gleischman, S. H. and Rowe, M. J.: Peyronie's disease: an electron microscopic study. J. Urol., 126: 333, 1981. 10. Serre, H., Izarn, P., Simon, L., Sany, J., Baldet, P. and Privat, J. M.: Calcinose circonscrite idiopathique. Presse Med., 77: 1529, 1969.