INT. J . HYPERTHERMIA,
1991, VOL. 7,
NO.
1, 221-230
Histopathology of prostatic tissue after transurethral hyperthermia J. LAUWERYNSt, L. BAERTS, J. VANDENHOVE? and Z. PETROVICHS TDepartment of Pathology, University Clinic St Rafael, Leuven, Belgium; *Department of Urology, University Clinic St Pieter, University of Leuven, Belgium; §Department of Radiation Oncology, University of Southern California School of Medicine, Los Angeles, California, USA
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
(Received22 January 1990; revision received I7 April 1990; accepted 25 April 1990) Histopathological changes were studied in four patients who had moderate to severe urinary outflow obstruction due to benign prostatic hyperplasia (BPH) and were treated with transurethral microwave hyperthermia (TUMH). All these patients received TUMH with a helical antenna using a BSD 300 unit. The temperature was controlled on the urethral surface at 45°C f 1"C. Each treatment session lasted 70 min at this temperature. Histological changes were periurethral, extending up to 6 mtn radially and 4-5 cm longitudinally. They were symmetrical and most severe in the immediate periurethral zone. The severity and distribution of these histological changes correlated well with the thermal profile of the helical antenna. Acute changes, observed 24-48 h following administration of a single TUMH session, consisted of periurethral oedema, parenchymal haemorrhages and occasional, partial small-vessel thrombosis. Selective coagulation necrosis of the parenchymal smooth muscles with sparing of smooth muscle fibres in the vessel walls was noted. Histopathological changes found in patients 7 or 26 days following the administration of 10 TUMH treatments given twice-weekly for 5 weeks showed more severe and deeper lesions. They consisted of interstitial haemorrhages, complete obliteration of blood vessel lumina due to thrombosis and further evidence of coagulation and haemorrhagic necrosis. Evidence of a reparative process with ingrowth of granulation tissue in various stages of organization was clearly demonstrated. The effect of TUMH on BPH-obstructed urethra is probably expressed through selective shrinking and retraction of the periurethral prostatic parenchyma due to organizing localized tissue necrosis and cicatrization. Details of this complex process will be presented.
1. Introduction Surgery is the standard treatment for patients with urinary outflow obstruction due to benign prostatic hypertrophy (BPH) (Graverson et al. 1989). In recent years hyperthennia HT) has been investigated as a non-invasive therapy for patients who are poor surgical risks o r for those who refuse surgical treatment fearing its complications. Transrectal HT has been used since the early 1980s. Several published reports showed good treatment tolerance, a low incidence of complications and major improvement in obstructive signs and symptoms in over 80% of patients (Lindner et al. 1987, Yerushalmi et al. 1985). Since the middle 1980s a new approach using transurethral microwave hyperthermia (TUMH) has been under investigation at the University of Southern California (USC) (Astrahan et al. 1989), and later at the Catholic University of Leuven (CUL) (Astrahan et al. 1991). A preliminary report of a Phase I study on the treatment of 2 1 patients showed excellent treatment tolerance, mild side-effects and an 80 % incidence of major improvement in objective study parameters (Sapozink et al. 1990). Of particular importance was a significant increase in urine flow rate and a decrease in residual volume. Address requests for reprints to: Prof. Dr J . Lauweryns, University Clinic St Rafael, Department of Pathology I, Minderbroedersstraat 12, B-3000, Leuven, Belgium. 0256-6736191 53 00 0,1991 Taylor & Francis Ltd
J . Lauweryns et al.
77'
i
&
C
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
There is a scarcity of data on pathological changes occurring in the prostate following TUMti. The purpose of this report is to present initial results of pathological examinations on prtjstatic tissue following TUMH. An attempt will be made to explain possible mechanisms of action of HT on BPH.
2. Materials and methods Bel-ween May and August 1989, 15 patients with moderate to severe urinary outflow obstruction were treated at CUL with TUMH in a Phase I study. This group included thrcx 120%) patients who had acute urinary retention. All patients were treated on an outpatient basis without sedation or anaesthesia. They received five to 10 treatments with a mean of 6 . 3 TUMH sessions. Each treatment lasted 70 min, given with a helical antenna at 915 MHz with a BSD 300 unit (BSD Medical Corporation, Salt Lake City, Utah). Tenipe:rature was monitored throughout the treatment session and maintained at 45 "C measured on the urethral surface. Details on thermometry and treatment technique have been presented elsewhere (Astrahan et al. 1990). Of the 15 patients treated, three (20%) failed TUMH. These included two patients who presented with acute urinary retention and one patient who had a neurogenic bladder with .3 ' 0 I residual volume. Following HT this was decreased to 1 -0 1. In the two patients who failed HT, retropubic prostatectomies were performed and the prostates were subjected 10 detailed pathological studies. These two patients received 10 TUMH sessions each. The treatrniints were given twice a week for 5 weeks and were separated by a minimum of 154 h (Table 1). In order to study acute post-TUMH histological changes in the prostate, two additional patients. who had severe urinary obstruction due to BPH and were scheduled to undergo rctropubic prostatectomy , were given a single HT treatment. This treatment was given Followimg careful explanation to the patients, and after obtaining informed consents. TUMH was given using the same methodology as in the 15 patients in the Phase I study. TUMH was fbllowed by surgery, 1 and 2 days, respectively. 'I'hc tour prostate specimens were subjected to macroscopic and careful microscopic ertamirhation. The weight o f the resected prostate specimens was as follows: Patient 1 , 117 g. Patient 2, 78 g; Patient 3 , 60 g; and Patient 4, 65 g. The glands were sectioned w e r j 5 mm perpendicular to the urethra. The prostatic slices were fixed in the standard li~rmalciehydeand/or Bouin's solution. Subsequently, they were stained with haematoxylin m d cosin. Special muscle and fibrin stains were used when indicated. 3 . Hest11ts Macroscopic examination of the prostate specimens obtained from the two patients who failed TUMH showed changes which could explain their treatment failure. Patient 3 had prominent hyperplasia of the middle lobe, which was protruding into the bladder and acting as a valve to urine flow. Patient 4 had markedly asymmetrical lateral lobes. In either case there %'assubstantial reduction in the area of coupling between BPH tissue and the helical antcnn;.l.
Table I .
Treatment schedule and interval from the last HT treatment to prostatectomy Hyperthermia (HT) ~
Patient Patient Patient Patient
1
2 3 4
1 session
1 session 10 sessions/S weeks 10 sessionsb weeks
Time to prostatectomy ____ 1 day 2 days I days 26 days
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
Histopathology of prostatic tissue after transurethral hyperthermia
223
The changes observed in the prostates of the four patients under study were symmetrical and periurethral. The most severe lesions were noted in the immediate vicinity of the prostatic urethra, particularly in its distal two-thirds. The bladder neck appeared nearly free of histological changes. Histological examination of the four resected prostates revealed a classic picture of prostatic hyperplasia with predominantly glandular proliferation. The histological picture of the prostates of Patients 1 and 2 (Table 1) was virtually identical, although somewhat more clearly expressed in Patient 2. Therefore, the microscopic picture presented here also represents that of Patient 1. In the periurethral corium of Patient 2, marked oedema and haemorrhages were observed. The oedema was extending further away radially from the urethra than were the interstitial haemorrhages (Figure 1). The immediately adjacent smooth muscle fibres showed early coagulation necrosis. There were shrunken pyknotic nuclei and intensely eosinophilic and homogeneous cytoplasm of the myocytes. This compared with lightly staining cytoplasm and viable appearing myocytes deeper within the prostate (Figure 2). The vessel walls and their smooth muscles were normal (Figure 1). In the immediate periurethral area, occasional early venular thrombosis can be observed (Figure 3). In one of the sections a rather dense lymphocytic infiltrate was seen in the corium. The periurethral prostatic ducts revealed no abnormalities. The macroscopic picture in Patient 3 illustrates well the distinctly symmetrical, periurethral changes (Figure 4). They were cup-shaped and consisted of dark and haemorrhagically infiltrated parenchyma. A clear margin was noted between these changes and normal-appearing parenchyma. They extended up to 3 mm radially from the urethra. No data exist concerning the extent of shrinkage of prostatic tissue subjected to fixation with formaldehyde. The best estimate on this tissue shrinkage, which was used in this
Figure 1. Patient 2: sections through periurethral tissue. The corium shows bleeding (B) and oedema (0);the latter extends between the underlying smooth muscle bundles. The urothelium is eroded. Vessel (*) walls are intact with patent lumina (H&E, X 112).
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
224
J . Lauweryns et al.
Fipuih. 2 . Pcrtient 2: shows superficial periurethral (right) and deep (left) smooth muscle fibres. 'l'he superficial fibres demonstrate coagulation necrosis. Cytoplasm is intensely eosinophilic ;ind the cell nuclei are pycnotic. This compares with viable smooth muscle fibres presenting lightly cosinophilic cytoplasm and vesicular nuclei (arrow) which are present further away t'r.oni the urethra (right) (H&E. X448).
study, is a 50% reduction in the diameter of the prostatic specimen. Therefore, the maximum radial tcxtent of severe changes was estimated to be 4-6 mm from the urethra. Microscopic examination of the dark areas observed macroscopically revealed the presence of complete haemorrhagic necrosis of the prostatic parenchyma, including the glands and ducts. There was thrombotic obliteration of blood vessels with necrosis of their walls (Figure 5). Deeper in the parenchyma these changes were less severe. They consisted of coagulation necrosis, which was limited to the smooth muscle fibres, or fibrinoid necrosis of the blood vessel walls without thrombotic obliteration of their lumina (Figure 5, inset). A sharp transition was present between the abnormal (fibrinoid necrosis) and normal walls of the wessels. C h i r evidence of a varying degree of organization by ingrowing granulation tissue was nclted. In the earliest stage this process was restricted to a band-like area, which extendcd along the border of the periurethral haemorrhagic necrotic zone. Progressively, the entire necrotic zone was infiltrated by ingrowing granulation tissue. Oedematous loose connective tissue was noted containing the same mononuclear cells and leukocytes as well as haemosiderin-laden macrophages and occasional collagen fibre deposits (Figure 6). In this stage of organization, early attempts of re-epithelialization of the urethra were present. Hislological changes in Patient 4 showed lesions to be generally more organized and advanced, although all phases of organization of granulation tissue could be seen (Figure 7 ) .The picture here consisted of several round and oval 'units'. These units had a central core trf cell-poor and organized fibrous tissue. Focal haemorrhages were occasionally noted. Likewise, occasional 'ghost' vessels with hyalinized walls and obliterated lumina could he obstrrved. These lumina were obliterated by loose connective tissue, which may have
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
Histopathology of prostatic tissue a f e r transurethral hyperthermia
225
Figure 3. Patient 2: sections through a superficial venule (right) demonstrate the presence of small thrombi. These thrombi are adhering to the damaged upper venular wall and are infiltrated by polyniorphs (inset). The other venules (left>appear normal. The upper corium is oedematous and nearly necrotic. Sparse lymphocytic infiltrates are present. The urothelium is eroded (U=urethra) (H&E, X 112; inset X282).
contained haemosiderin-laden macrophages. They probably represented the final stages of organization of thrombosed and necrotic blood vessels (Figure 8). 4. Discussion The periurethral location and symmetrical distribution of histological lesions, as noted in the four patients in this study, corresponded well with the radial thermal profile of the helical antenna (Satoh et al. 1984, Astrahan et al. 1990). This antenna showed the highest temperature immediately adjacent to the catheter, and rapid temperature decrease radially. The temperature of 45-46"C, as typically measured on the urethral surface in this Phase I study, was expected to result in a minimum temperature of 42°C 5-6 mm radially from the surface of the urethra (Astrahan et al. 1989, 1990). The longitudinal temperature profile of the antenna, again, correlated very well with the presence and severity of histological changes. The parenchymal oedema and interstitial haemorrhages seen in the two patients, 1 o r 2 days following a single TUMH session, probably resulted from vascular damage. One of the manifestations of this damage was increased endothelial permeability. This permeability initially allowed for extravasation of serum, and in a later stage with increasing endothelial damage, also allowed for extravasation of cellular elements, and finally led to thrombosis. This sequence of events following administration of HT has been observed by other investigators (Meshorer et al. 1983, Emami and Song 1984, Nilsen 1984). The necrosis of the smooth muscle fibres was most likely due to the dynamics of heat transfer in vivu. The histological lesions observed in Patients 1 and 2 corresponded well with the tissue
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
226
J . Lauweryns et al.
Figure 4.. Patient 3: cross-section of the periurethral prostatic parenchyma. Clearly visible dark haemorrhagic lesions with maximal radial distance from the urethra of 3 mm. Lesions are ~op-shapedwith a slight central excavation. Macroscopic picture. Specimen fixed in kimmaldehyde.
t3gut-c 5. Patient 3: sections through the periurethral parenchyma as seen in Figure 4. Blood vessels : i x completely thrombosed (T) and there is marked interstitial bleeding (R). The superficial i ~ e t h r a larea shows necrosis with eroded urothelium. (H&E. X 38).
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
Histopathology of prostatic tissue a f e r transurethral hyperthermia
227
Figure 6. Patient 3: the organizing part of periurethral parenchyma shows nearly complete ingrowth by granulation tissue. Small blood vessels and nuclei of young fibroblasts are clearly demonstrated. There is a discrete mononuclear cell infiltrate. The commencement of urethral re-epithelialization is noted (H&E, X 112). findings studied after a similar time interval following HT exposure in rats (Badylack et al. 1985). Similar data were obtained in pig experiments (Meshorer et al. 1983, Fajardo et at. 1984, Martinez et al. 1984, Higgins et al. 1988). It is of interest to note the preservation of smooth muscles in blood vessel walls in the area which clearly showed necrosis of the musculature of the prostatic parenchyma. A probable explanation for this phenomenon was the cooling effect of blood flow in the lumina of blood vessels, which protected the vessel wall myocytes from more severe heat damage (Emami and Song 1983, Song 1984). This blood flow, which is enhanced by increased tissue temperature, although able to sufficiently cool vessel walls is probably insufficient to protect the smooth muscle fibres in the surrounding tissues. HT-induced increase in local blood flow may also explain the presence of more superficial changes in the periurethral tissues following a single HT treatment, in contrast to the much deeper changes following multiple HT sessions. Additionally, with each subsequent TUMH treatment, more vascular wall damage and thrombosis accumulated, resulting in a decreased ability to perfuse and cool the prostate parenchyma. This, in turn, makes the parenchyma more vulnerable to HT and allows more heat damage to the tissues further away from the urethra (Freeman et al. 1980, Gerweck et al. 1980, Emami and Song 1984). The progressive increase in the degree of parenchymal injury and the increase in the depth of HT penetration was illustrated well in Figure 5. In the deep margin of the section shown in Figure 5 there is fibrinoid vessel wall necrosis with focal parenchymal haemorrhages and smooth muscle necrosis. These changes represented the first major step in the expression of progressive HT damage. These were followed by complete haemorrhagic vascular wall necrosis with concomitant thrombosis as noted in the periurethral areas. The complete lytic necrosis in the immediate periurethral zone probably represented the most advanced stage of this progressive HT damage.
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
128
J . Lauweryns et al.
f;igurc '7. Ptrtimt 4: the necrotic prostatic parenchyma is being replaced by the capillary-rich 21-anulation tissue (0)and it becomes collagenized (*). Urethra (U) (H&E. X28).
The process discussed above was similar to the changes presented by Leib et af. 1986. This was particularly true following the administration of six HT sessions at 45-5"C for 1 - 5 h given at 48-72 h intervals. Although Leib et al. used a transrectal HT approach, they reported haemorrhagic tissue necrosis in the area of the prostatic urethra. This corresponded to the changes seen in our patients. Interestingly, the presence of these severe change(; some distance from the rectal applicator may suggest a greater degree of heat sensitivity of the periurethral tissue, as compared with the remaining prostatic parenchyma. The final histological changes observed in our patients following TUMH were represeinted by ingrowing granulation tissue with its organization and, lastly, fibrosis. This pxicess was described as a late effect of HT in murine epidermis after 2-3 weeks (Haverman or (11. I '988) and in pig mesenchymal tissues 28-3 1 days after HT (Meshorer et al. 1983 Fajardo ct (21. 1984). More work is needed to confirm our histological findings, and to study tissue changes in the p'rostate following administration of TUMH. Of particular interest would be a study correlating the severity of histological changes with tissue temperature measured inrerstii.ially during the treatment session. I
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
Histopathology of prostatic tissue after transurethral hyperthermia
229
Figure 8. Patient 4: larger blood vessels located deep in periurethral tissue with completely hyalinized walls (*). The vessel lumina are obliterated by loose connective tissue containing haemosiderin!aden macrophages (arrow). This picture represents organized thrombosis (H&E, X 1 12).
References ASTRAHAN, M., IMANAKA, K., JOZSEF,G., AMEYE,F., BAERT,L., SAPOZINK, M. D., BOYD,S., and PETROVICH, Z., 1991, Heating characteristics of helical microwave applicator for transurethral hyperthermia of benign prostatic hyperplasia. International Journal of Hyperthermia, 7 , 141-156. ASTRAHAN, M., SAPOZINK, M. D., COHEN,D., LUXTON,G., KAMPP,T., BOYD,S., PETROVICH, Z., 1989, Microwave applicator for transurethral hyperthermia of benign prostatic hyperplasia. International Journal of Hyperthennia, 5, 283-296. BADYLACK, S. F., BABBS,C. F., SKOJAC,T. M., VOORHEES, W. D., and RICHARDSON, R. C., 1985, Hyperthermia-induced vascular injury in normal and neoplastic tissue. Cancer, 56, 99 1- 1000. EMAMI,B., and SONG,C. W., 1984, Physiological mechanisms in hyperthermia: A review. International Journal of Radiation Oncology, Biology, Physics, 10, 289-295. L. F., 1984, Pathological effects of hyperthermia in normal tissues. Cancer Research, FAJARDO, 44, (SUPPI.), 4826-4835. FAJARDO, L. F., MEYER,J. L., MESHORER, A., PRIONAS, S., MARTINEZ, A. A,, and HAHN,G. M., 1984, Thermal injury and thermotolerance in mesenchymal tissues. Frontiers in Radiation Therapy and Oncology, 18, 144-152. FREEMAN, M. L., RAAPHORST, G. P., HOPWOOD,L. E., and DEWEY,W. C., 1980, The effect of pH on cell lethality induced by hyperthermic treatment. Cancer, 45, 2291-2300. GERWECK, L. E., JENNINGS, M., RICHARDS, B., and RICHARDS, B., 1980, Influence of pH on the response of cells to single and split doses of hyperthermia. Cancer Research, 4,4019-4024. F., ~ ~ ~ B R U S K E WR.I T C., Z ,1989, GRAVERSON, P. H., GASSER,T. C., WASSON,J. H., HINMAN, Controversies about indications for transurethral resection of the prostate. Journal of Urology, 141, 475-481. HAVERMAN, J., JANSEN,W., WONDERGEM, J., and BEGG,A. C., 1988, Cell proliferation in the murine epidermis and subcutaneous vascular endothelium after hyperthermia. International Journal of Radiation Biology, 54, 105-1 13. HIGGINS,P. D., ADAMS,W. M., and DUBIELZIG,R. R., 1988, Thermal dosimetry of normal porcine tissue. Radiation Research, 114, 225-230.
230
J . Luuweryns et al.
RATHEM,A,, and SERVADIO,C., 1986, Histopathological observations in the canine prostate treated by local microwave hyperthermia. Prostate, 8, 93- 102. ~ , I N l l N E R . A , , GOLOMB,J., SIEGEL,Y., and LEV, A , , 1987, Local hyperthermia of the prostate gland for the treatment of benign prostatic hypertrophy and urinary retention. A preliminary report. British Journal of Urology, 60, 567-571. M A R ~ I N EA. Z , A,. MESHORER, A , , MEYER,J. L., HAHN,G. M., FAJARDO,L. F., and PRIONAS. S . D., 1983, Thermal sensitivity and thermotolerance in normal porcine tissue. Cancer .Research, 43, 2072-2075. MESHORER. A , , PRIONAS,S. D., FAJARDO,L. F., MEYER,J. L., HAHN,G. M., and MARTINEL, A. A , , 1983, The effects of hyperthermia on normal mesenchymal tissues. Archives of Puthology and Laboratory Medicine, 107, 328-339. NII.SEIV.N. O., 1984, Endothelial changes and microvascular leakage due to hyperthermia in chick embryos. Virchows Archives of Cell Pathology, 46, 165-1 74. SAPOZINK, M. D., BOYD,S., ASTRAHAN, M., JOZSEF,G., and PETROVICH, Z . , 1990, Transurethral hyperthermia for benign prostatic hyperplasia-preliminary clinical results. Journal qf Urolog,,
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
l.,ti~. Z..
IJFFEK, P. R., and FIKE, J. R., 1984, Thermal distribution studies of helical coil microwave antennas for interstitial hyperthermia. International Journal of Radiation Oncologx, B / O / O ~ JPhpic.y, J, 10, 2155-2162. , C. W., 1984, Effect of local hyperthermia on blood flow and microenvironment: a review. Cancer Research, 44,47218-4730s. YEIIU:.:HALMI, A,, FISKEI~OVITZ, Y., SINGER,D., REINER,I., ARIELLY,J., ABRAMOVICI, Y., CATSENELSON. R., LEVY,E., and SHANI,A., 1985, Localized deep microwave hyperthermia in thc treatment of poor operative risk patients with benign prostatic hyperplasia. Joi~rnt~l ~ !Uf I Y ~ O133, ~ ~873--876. ,
1991, VOL. 7,
NO.
1, 221-230
Histopathology of prostatic tissue after transurethral hyperthermia J. LAUWERYNSt, L. BAERTS, J. VANDENHOVE? and Z. PETROVICHS TDepartment of Pathology, University Clinic St Rafael, Leuven, Belgium; *Department of Urology, University Clinic St Pieter, University of Leuven, Belgium; §Department of Radiation Oncology, University of Southern California School of Medicine, Los Angeles, California, USA
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
(Received22 January 1990; revision received I7 April 1990; accepted 25 April 1990) Histopathological changes were studied in four patients who had moderate to severe urinary outflow obstruction due to benign prostatic hyperplasia (BPH) and were treated with transurethral microwave hyperthermia (TUMH). All these patients received TUMH with a helical antenna using a BSD 300 unit. The temperature was controlled on the urethral surface at 45°C f 1"C. Each treatment session lasted 70 min at this temperature. Histological changes were periurethral, extending up to 6 mtn radially and 4-5 cm longitudinally. They were symmetrical and most severe in the immediate periurethral zone. The severity and distribution of these histological changes correlated well with the thermal profile of the helical antenna. Acute changes, observed 24-48 h following administration of a single TUMH session, consisted of periurethral oedema, parenchymal haemorrhages and occasional, partial small-vessel thrombosis. Selective coagulation necrosis of the parenchymal smooth muscles with sparing of smooth muscle fibres in the vessel walls was noted. Histopathological changes found in patients 7 or 26 days following the administration of 10 TUMH treatments given twice-weekly for 5 weeks showed more severe and deeper lesions. They consisted of interstitial haemorrhages, complete obliteration of blood vessel lumina due to thrombosis and further evidence of coagulation and haemorrhagic necrosis. Evidence of a reparative process with ingrowth of granulation tissue in various stages of organization was clearly demonstrated. The effect of TUMH on BPH-obstructed urethra is probably expressed through selective shrinking and retraction of the periurethral prostatic parenchyma due to organizing localized tissue necrosis and cicatrization. Details of this complex process will be presented.
1. Introduction Surgery is the standard treatment for patients with urinary outflow obstruction due to benign prostatic hypertrophy (BPH) (Graverson et al. 1989). In recent years hyperthennia HT) has been investigated as a non-invasive therapy for patients who are poor surgical risks o r for those who refuse surgical treatment fearing its complications. Transrectal HT has been used since the early 1980s. Several published reports showed good treatment tolerance, a low incidence of complications and major improvement in obstructive signs and symptoms in over 80% of patients (Lindner et al. 1987, Yerushalmi et al. 1985). Since the middle 1980s a new approach using transurethral microwave hyperthermia (TUMH) has been under investigation at the University of Southern California (USC) (Astrahan et al. 1989), and later at the Catholic University of Leuven (CUL) (Astrahan et al. 1991). A preliminary report of a Phase I study on the treatment of 2 1 patients showed excellent treatment tolerance, mild side-effects and an 80 % incidence of major improvement in objective study parameters (Sapozink et al. 1990). Of particular importance was a significant increase in urine flow rate and a decrease in residual volume. Address requests for reprints to: Prof. Dr J . Lauweryns, University Clinic St Rafael, Department of Pathology I, Minderbroedersstraat 12, B-3000, Leuven, Belgium. 0256-6736191 53 00 0,1991 Taylor & Francis Ltd
J . Lauweryns et al.
77'
i
&
C
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
There is a scarcity of data on pathological changes occurring in the prostate following TUMti. The purpose of this report is to present initial results of pathological examinations on prtjstatic tissue following TUMH. An attempt will be made to explain possible mechanisms of action of HT on BPH.
2. Materials and methods Bel-ween May and August 1989, 15 patients with moderate to severe urinary outflow obstruction were treated at CUL with TUMH in a Phase I study. This group included thrcx 120%) patients who had acute urinary retention. All patients were treated on an outpatient basis without sedation or anaesthesia. They received five to 10 treatments with a mean of 6 . 3 TUMH sessions. Each treatment lasted 70 min, given with a helical antenna at 915 MHz with a BSD 300 unit (BSD Medical Corporation, Salt Lake City, Utah). Tenipe:rature was monitored throughout the treatment session and maintained at 45 "C measured on the urethral surface. Details on thermometry and treatment technique have been presented elsewhere (Astrahan et al. 1990). Of the 15 patients treated, three (20%) failed TUMH. These included two patients who presented with acute urinary retention and one patient who had a neurogenic bladder with .3 ' 0 I residual volume. Following HT this was decreased to 1 -0 1. In the two patients who failed HT, retropubic prostatectomies were performed and the prostates were subjected 10 detailed pathological studies. These two patients received 10 TUMH sessions each. The treatrniints were given twice a week for 5 weeks and were separated by a minimum of 154 h (Table 1). In order to study acute post-TUMH histological changes in the prostate, two additional patients. who had severe urinary obstruction due to BPH and were scheduled to undergo rctropubic prostatectomy , were given a single HT treatment. This treatment was given Followimg careful explanation to the patients, and after obtaining informed consents. TUMH was given using the same methodology as in the 15 patients in the Phase I study. TUMH was fbllowed by surgery, 1 and 2 days, respectively. 'I'hc tour prostate specimens were subjected to macroscopic and careful microscopic ertamirhation. The weight o f the resected prostate specimens was as follows: Patient 1 , 117 g. Patient 2, 78 g; Patient 3 , 60 g; and Patient 4, 65 g. The glands were sectioned w e r j 5 mm perpendicular to the urethra. The prostatic slices were fixed in the standard li~rmalciehydeand/or Bouin's solution. Subsequently, they were stained with haematoxylin m d cosin. Special muscle and fibrin stains were used when indicated. 3 . Hest11ts Macroscopic examination of the prostate specimens obtained from the two patients who failed TUMH showed changes which could explain their treatment failure. Patient 3 had prominent hyperplasia of the middle lobe, which was protruding into the bladder and acting as a valve to urine flow. Patient 4 had markedly asymmetrical lateral lobes. In either case there %'assubstantial reduction in the area of coupling between BPH tissue and the helical antcnn;.l.
Table I .
Treatment schedule and interval from the last HT treatment to prostatectomy Hyperthermia (HT) ~
Patient Patient Patient Patient
1
2 3 4
1 session
1 session 10 sessions/S weeks 10 sessionsb weeks
Time to prostatectomy ____ 1 day 2 days I days 26 days
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
Histopathology of prostatic tissue after transurethral hyperthermia
223
The changes observed in the prostates of the four patients under study were symmetrical and periurethral. The most severe lesions were noted in the immediate vicinity of the prostatic urethra, particularly in its distal two-thirds. The bladder neck appeared nearly free of histological changes. Histological examination of the four resected prostates revealed a classic picture of prostatic hyperplasia with predominantly glandular proliferation. The histological picture of the prostates of Patients 1 and 2 (Table 1) was virtually identical, although somewhat more clearly expressed in Patient 2. Therefore, the microscopic picture presented here also represents that of Patient 1. In the periurethral corium of Patient 2, marked oedema and haemorrhages were observed. The oedema was extending further away radially from the urethra than were the interstitial haemorrhages (Figure 1). The immediately adjacent smooth muscle fibres showed early coagulation necrosis. There were shrunken pyknotic nuclei and intensely eosinophilic and homogeneous cytoplasm of the myocytes. This compared with lightly staining cytoplasm and viable appearing myocytes deeper within the prostate (Figure 2). The vessel walls and their smooth muscles were normal (Figure 1). In the immediate periurethral area, occasional early venular thrombosis can be observed (Figure 3). In one of the sections a rather dense lymphocytic infiltrate was seen in the corium. The periurethral prostatic ducts revealed no abnormalities. The macroscopic picture in Patient 3 illustrates well the distinctly symmetrical, periurethral changes (Figure 4). They were cup-shaped and consisted of dark and haemorrhagically infiltrated parenchyma. A clear margin was noted between these changes and normal-appearing parenchyma. They extended up to 3 mm radially from the urethra. No data exist concerning the extent of shrinkage of prostatic tissue subjected to fixation with formaldehyde. The best estimate on this tissue shrinkage, which was used in this
Figure 1. Patient 2: sections through periurethral tissue. The corium shows bleeding (B) and oedema (0);the latter extends between the underlying smooth muscle bundles. The urothelium is eroded. Vessel (*) walls are intact with patent lumina (H&E, X 112).
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
224
J . Lauweryns et al.
Fipuih. 2 . Pcrtient 2: shows superficial periurethral (right) and deep (left) smooth muscle fibres. 'l'he superficial fibres demonstrate coagulation necrosis. Cytoplasm is intensely eosinophilic ;ind the cell nuclei are pycnotic. This compares with viable smooth muscle fibres presenting lightly cosinophilic cytoplasm and vesicular nuclei (arrow) which are present further away t'r.oni the urethra (right) (H&E. X448).
study, is a 50% reduction in the diameter of the prostatic specimen. Therefore, the maximum radial tcxtent of severe changes was estimated to be 4-6 mm from the urethra. Microscopic examination of the dark areas observed macroscopically revealed the presence of complete haemorrhagic necrosis of the prostatic parenchyma, including the glands and ducts. There was thrombotic obliteration of blood vessels with necrosis of their walls (Figure 5). Deeper in the parenchyma these changes were less severe. They consisted of coagulation necrosis, which was limited to the smooth muscle fibres, or fibrinoid necrosis of the blood vessel walls without thrombotic obliteration of their lumina (Figure 5, inset). A sharp transition was present between the abnormal (fibrinoid necrosis) and normal walls of the wessels. C h i r evidence of a varying degree of organization by ingrowing granulation tissue was nclted. In the earliest stage this process was restricted to a band-like area, which extendcd along the border of the periurethral haemorrhagic necrotic zone. Progressively, the entire necrotic zone was infiltrated by ingrowing granulation tissue. Oedematous loose connective tissue was noted containing the same mononuclear cells and leukocytes as well as haemosiderin-laden macrophages and occasional collagen fibre deposits (Figure 6). In this stage of organization, early attempts of re-epithelialization of the urethra were present. Hislological changes in Patient 4 showed lesions to be generally more organized and advanced, although all phases of organization of granulation tissue could be seen (Figure 7 ) .The picture here consisted of several round and oval 'units'. These units had a central core trf cell-poor and organized fibrous tissue. Focal haemorrhages were occasionally noted. Likewise, occasional 'ghost' vessels with hyalinized walls and obliterated lumina could he obstrrved. These lumina were obliterated by loose connective tissue, which may have
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
Histopathology of prostatic tissue a f e r transurethral hyperthermia
225
Figure 3. Patient 2: sections through a superficial venule (right) demonstrate the presence of small thrombi. These thrombi are adhering to the damaged upper venular wall and are infiltrated by polyniorphs (inset). The other venules (left>appear normal. The upper corium is oedematous and nearly necrotic. Sparse lymphocytic infiltrates are present. The urothelium is eroded (U=urethra) (H&E, X 112; inset X282).
contained haemosiderin-laden macrophages. They probably represented the final stages of organization of thrombosed and necrotic blood vessels (Figure 8). 4. Discussion The periurethral location and symmetrical distribution of histological lesions, as noted in the four patients in this study, corresponded well with the radial thermal profile of the helical antenna (Satoh et al. 1984, Astrahan et al. 1990). This antenna showed the highest temperature immediately adjacent to the catheter, and rapid temperature decrease radially. The temperature of 45-46"C, as typically measured on the urethral surface in this Phase I study, was expected to result in a minimum temperature of 42°C 5-6 mm radially from the surface of the urethra (Astrahan et al. 1989, 1990). The longitudinal temperature profile of the antenna, again, correlated very well with the presence and severity of histological changes. The parenchymal oedema and interstitial haemorrhages seen in the two patients, 1 o r 2 days following a single TUMH session, probably resulted from vascular damage. One of the manifestations of this damage was increased endothelial permeability. This permeability initially allowed for extravasation of serum, and in a later stage with increasing endothelial damage, also allowed for extravasation of cellular elements, and finally led to thrombosis. This sequence of events following administration of HT has been observed by other investigators (Meshorer et al. 1983, Emami and Song 1984, Nilsen 1984). The necrosis of the smooth muscle fibres was most likely due to the dynamics of heat transfer in vivu. The histological lesions observed in Patients 1 and 2 corresponded well with the tissue
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
226
J . Lauweryns et al.
Figure 4.. Patient 3: cross-section of the periurethral prostatic parenchyma. Clearly visible dark haemorrhagic lesions with maximal radial distance from the urethra of 3 mm. Lesions are ~op-shapedwith a slight central excavation. Macroscopic picture. Specimen fixed in kimmaldehyde.
t3gut-c 5. Patient 3: sections through the periurethral parenchyma as seen in Figure 4. Blood vessels : i x completely thrombosed (T) and there is marked interstitial bleeding (R). The superficial i ~ e t h r a larea shows necrosis with eroded urothelium. (H&E. X 38).
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
Histopathology of prostatic tissue a f e r transurethral hyperthermia
227
Figure 6. Patient 3: the organizing part of periurethral parenchyma shows nearly complete ingrowth by granulation tissue. Small blood vessels and nuclei of young fibroblasts are clearly demonstrated. There is a discrete mononuclear cell infiltrate. The commencement of urethral re-epithelialization is noted (H&E, X 112). findings studied after a similar time interval following HT exposure in rats (Badylack et al. 1985). Similar data were obtained in pig experiments (Meshorer et al. 1983, Fajardo et at. 1984, Martinez et al. 1984, Higgins et al. 1988). It is of interest to note the preservation of smooth muscles in blood vessel walls in the area which clearly showed necrosis of the musculature of the prostatic parenchyma. A probable explanation for this phenomenon was the cooling effect of blood flow in the lumina of blood vessels, which protected the vessel wall myocytes from more severe heat damage (Emami and Song 1983, Song 1984). This blood flow, which is enhanced by increased tissue temperature, although able to sufficiently cool vessel walls is probably insufficient to protect the smooth muscle fibres in the surrounding tissues. HT-induced increase in local blood flow may also explain the presence of more superficial changes in the periurethral tissues following a single HT treatment, in contrast to the much deeper changes following multiple HT sessions. Additionally, with each subsequent TUMH treatment, more vascular wall damage and thrombosis accumulated, resulting in a decreased ability to perfuse and cool the prostate parenchyma. This, in turn, makes the parenchyma more vulnerable to HT and allows more heat damage to the tissues further away from the urethra (Freeman et al. 1980, Gerweck et al. 1980, Emami and Song 1984). The progressive increase in the degree of parenchymal injury and the increase in the depth of HT penetration was illustrated well in Figure 5. In the deep margin of the section shown in Figure 5 there is fibrinoid vessel wall necrosis with focal parenchymal haemorrhages and smooth muscle necrosis. These changes represented the first major step in the expression of progressive HT damage. These were followed by complete haemorrhagic vascular wall necrosis with concomitant thrombosis as noted in the periurethral areas. The complete lytic necrosis in the immediate periurethral zone probably represented the most advanced stage of this progressive HT damage.
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
128
J . Lauweryns et al.
f;igurc '7. Ptrtimt 4: the necrotic prostatic parenchyma is being replaced by the capillary-rich 21-anulation tissue (0)and it becomes collagenized (*). Urethra (U) (H&E. X28).
The process discussed above was similar to the changes presented by Leib et af. 1986. This was particularly true following the administration of six HT sessions at 45-5"C for 1 - 5 h given at 48-72 h intervals. Although Leib et al. used a transrectal HT approach, they reported haemorrhagic tissue necrosis in the area of the prostatic urethra. This corresponded to the changes seen in our patients. Interestingly, the presence of these severe change(; some distance from the rectal applicator may suggest a greater degree of heat sensitivity of the periurethral tissue, as compared with the remaining prostatic parenchyma. The final histological changes observed in our patients following TUMH were represeinted by ingrowing granulation tissue with its organization and, lastly, fibrosis. This pxicess was described as a late effect of HT in murine epidermis after 2-3 weeks (Haverman or (11. I '988) and in pig mesenchymal tissues 28-3 1 days after HT (Meshorer et al. 1983 Fajardo ct (21. 1984). More work is needed to confirm our histological findings, and to study tissue changes in the p'rostate following administration of TUMH. Of particular interest would be a study correlating the severity of histological changes with tissue temperature measured inrerstii.ially during the treatment session. I
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
Histopathology of prostatic tissue after transurethral hyperthermia
229
Figure 8. Patient 4: larger blood vessels located deep in periurethral tissue with completely hyalinized walls (*). The vessel lumina are obliterated by loose connective tissue containing haemosiderin!aden macrophages (arrow). This picture represents organized thrombosis (H&E, X 1 12).
References ASTRAHAN, M., IMANAKA, K., JOZSEF,G., AMEYE,F., BAERT,L., SAPOZINK, M. D., BOYD,S., and PETROVICH, Z., 1991, Heating characteristics of helical microwave applicator for transurethral hyperthermia of benign prostatic hyperplasia. International Journal of Hyperthermia, 7 , 141-156. ASTRAHAN, M., SAPOZINK, M. D., COHEN,D., LUXTON,G., KAMPP,T., BOYD,S., PETROVICH, Z., 1989, Microwave applicator for transurethral hyperthermia of benign prostatic hyperplasia. International Journal of Hyperthennia, 5, 283-296. BADYLACK, S. F., BABBS,C. F., SKOJAC,T. M., VOORHEES, W. D., and RICHARDSON, R. C., 1985, Hyperthermia-induced vascular injury in normal and neoplastic tissue. Cancer, 56, 99 1- 1000. EMAMI,B., and SONG,C. W., 1984, Physiological mechanisms in hyperthermia: A review. International Journal of Radiation Oncology, Biology, Physics, 10, 289-295. L. F., 1984, Pathological effects of hyperthermia in normal tissues. Cancer Research, FAJARDO, 44, (SUPPI.), 4826-4835. FAJARDO, L. F., MEYER,J. L., MESHORER, A., PRIONAS, S., MARTINEZ, A. A,, and HAHN,G. M., 1984, Thermal injury and thermotolerance in mesenchymal tissues. Frontiers in Radiation Therapy and Oncology, 18, 144-152. FREEMAN, M. L., RAAPHORST, G. P., HOPWOOD,L. E., and DEWEY,W. C., 1980, The effect of pH on cell lethality induced by hyperthermic treatment. Cancer, 45, 2291-2300. GERWECK, L. E., JENNINGS, M., RICHARDS, B., and RICHARDS, B., 1980, Influence of pH on the response of cells to single and split doses of hyperthermia. Cancer Research, 4,4019-4024. F., ~ ~ ~ B R U S K E WR.I T C., Z ,1989, GRAVERSON, P. H., GASSER,T. C., WASSON,J. H., HINMAN, Controversies about indications for transurethral resection of the prostate. Journal of Urology, 141, 475-481. HAVERMAN, J., JANSEN,W., WONDERGEM, J., and BEGG,A. C., 1988, Cell proliferation in the murine epidermis and subcutaneous vascular endothelium after hyperthermia. International Journal of Radiation Biology, 54, 105-1 13. HIGGINS,P. D., ADAMS,W. M., and DUBIELZIG,R. R., 1988, Thermal dosimetry of normal porcine tissue. Radiation Research, 114, 225-230.
230
J . Luuweryns et al.
RATHEM,A,, and SERVADIO,C., 1986, Histopathological observations in the canine prostate treated by local microwave hyperthermia. Prostate, 8, 93- 102. ~ , I N l l N E R . A , , GOLOMB,J., SIEGEL,Y., and LEV, A , , 1987, Local hyperthermia of the prostate gland for the treatment of benign prostatic hypertrophy and urinary retention. A preliminary report. British Journal of Urology, 60, 567-571. M A R ~ I N EA. Z , A,. MESHORER, A , , MEYER,J. L., HAHN,G. M., FAJARDO,L. F., and PRIONAS. S . D., 1983, Thermal sensitivity and thermotolerance in normal porcine tissue. Cancer .Research, 43, 2072-2075. MESHORER. A , , PRIONAS,S. D., FAJARDO,L. F., MEYER,J. L., HAHN,G. M., and MARTINEL, A. A , , 1983, The effects of hyperthermia on normal mesenchymal tissues. Archives of Puthology and Laboratory Medicine, 107, 328-339. NII.SEIV.N. O., 1984, Endothelial changes and microvascular leakage due to hyperthermia in chick embryos. Virchows Archives of Cell Pathology, 46, 165-1 74. SAPOZINK, M. D., BOYD,S., ASTRAHAN, M., JOZSEF,G., and PETROVICH, Z . , 1990, Transurethral hyperthermia for benign prostatic hyperplasia-preliminary clinical results. Journal qf Urolog,,
Int J Hyperthermia Downloaded from informahealthcare.com by University of Newcastle on 01/05/15 For personal use only.
l.,ti~. Z..
IJFFEK, P. R., and FIKE, J. R., 1984, Thermal distribution studies of helical coil microwave antennas for interstitial hyperthermia. International Journal of Radiation Oncologx, B / O / O ~ JPhpic.y, J, 10, 2155-2162. , C. W., 1984, Effect of local hyperthermia on blood flow and microenvironment: a review. Cancer Research, 44,47218-4730s. YEIIU:.:HALMI, A,, FISKEI~OVITZ, Y., SINGER,D., REINER,I., ARIELLY,J., ABRAMOVICI, Y., CATSENELSON. R., LEVY,E., and SHANI,A., 1985, Localized deep microwave hyperthermia in thc treatment of poor operative risk patients with benign prostatic hyperplasia. Joi~rnt~l ~ !Uf I Y ~ O133, ~ ~873--876. ,
