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Re: The Ultrastructural Changes of Prostate Adenocarcinoma Following External Beam Radiation Therapy
Vol. 124, September
0022-534 7/80/1242-0433$02.00/0
Printed in U.S.A.
THE ,JoURNAL OF UROLOGY
Copyright © 1980 by The Williams & Wilkins Co.
Letters to the Editor IDIOPATHIC RETROPEHITONEAL FIBROSIS
To the Editor. In the excellent review article by Lepor and Walsh the association of retroperitoneal fibrosis with other forms of sclerosing fibrosis, vasculitis and collagen vascular-like processes, for example Weber-Christian disease, was indicated and supported by a large number of individual case reports. 1 An additional possible association of retroperitoneal fibrosis with a vascular necrosis of the femoral head has been reported.'·" In these 2 case reports both patients were women and had femoral head necrosis on the same side as the respective unilateral retroperitoneal fibrosis, an entity that is reported as unilateral in only 25 per cent of the cases.4 In consideration of the possible relationship certain variables were excluded that are known to be associated with retroperitoneal fibrosis or femoral head necrosis, such as the use of methysergide or corticosteroids. Since the origin of both entities was undetermined one also must consider these 2 entities as possibly because of a generalized collagen disease, vasculitis, hypersensitivity state or autoimmune reaction. Respectfully, Rodney A. Appell Department of Urology Louisiana State University Medical Center New Orleans, Louisiana 70112
ticated electron microscope, detect at the time when the cells are not in mitosis morphological changes that will alter the cell's future reproductive capabilities? This appears to be a formidable task. The authors state that "of the 6 patients with definitive evidence of either recurrent or continued malignancy after radiation the ultrastructural appearance of the tumor was indistinguishable untreated carcinoma, suggesting that the tumor cells were still viable". The only definitive evidence of recurrent or continued malignancy can be, by definition, its regrowth. The authors also remark that totally benign-appearing epithelium was observed in patients with no evidence of tumor after irradiation. They cite this finding as evidence that there is regrowth of normal prostatic epithelium after the malignancy has been eradicated. This is hardly surprising since a certain degree of repopulation occurs normally in irradiated tissues. Indeed, differential recovery is one of the fundamental processes upon which radiation therapy is based, for it enables one to eradicate the tumor while preserving normal tissues." We must agree with Doctor Mostofi's editorial comment that morphological determination of tumor cell viability would be highly desirable but that electron microscopy appears to be of little value in achieving such a goal. Respectfully, Miljenko V. Pilepich and Carleton C. Stewart Division of Radiation Oncology Washington University School of Medicine St Louis, Missouri 63108
1. Lepor, H. and Walsh, P. C.: Idiopathic retroperitoneal fibrosis. J.
Urol., 122: 1, 1979. 2. n..,uuua1. B. A.: A vascular necrosis of the head of the femur in a case retroperitoneal fibrosis. Postgrad. Med. J., 49: 59, 1973. 3. Appell, R. A. and Weiss, R. M.: Retroperitoneal fibrosis and avascular necrosis of the femoral head. J.A.M.A., 236: 2886, 1976. 4. Watts, H. G.: Retroperitoneal fibrosis. New Zeal. Med. J., 79: 247, 1973.
1. Andrews, J. R.: Cell killing by ionizing radiation. The
mechanism of cell killing. In: The Radio biology of Human Radiotherapy. Philadelphia: W. B. Saunders Co., chapt. 2, p. 15, 1968. 2. Andrews, J. R.: Cell populations. In: The Radiobiology of Human Cancer Radiotherapy. Philadelphia: W. B. Saunders Co., chapt. 5, pp. 58-94, 1968.
RE: THE ULTRASTRUCTURAL CHANGES OF PROSTATE ADENOCARCINOMA FOLLOWING EXTERNAL BEAM RADIATION THERAPY V. J. Kiesling, H.
Friedman, J. W. McAninch, D. A. Nachtsheim and T. J. Nemeth J. Urol., 122: 633-636, 1979
To the Editor. One of the aims of the study by Kiesling and associates was to "develop a set ofultrastructural criteria that will aid the clinician and pathologist in the detection of active, recurrent or residual carcinoma after radiation therapy". We believe it appropriate to point out statements in this report reflecting misconceptions of basic tumor biology and radiation effects on tumor and normal tissues. To be truly useful the test (electron microscopy) must be able to distinguish clonogenic tumor cells after irradiation. Viability, in this context, implies the surviving cell's capacity to produce new clones of tumor cells and not simply the cell's ability to remain metabolically active as suggested in the authors' introduction. The fundamental target of radiation is the cell's genetic material, the deoxyribonucleic acid molecule. 1 By inducing alterations in the structure of the cell's deoxyribonucleic acid radiation deprives the cell of its reproductive capability. Thus, while cells may accumulate lethal damin any phase of the cell cycle it is most often expressed during Tumors with a low growth fraction (slow growing tumors) may take longer to regress because the cells are not cycling and, therefore, do not express the accumulated lethal damage. This is one reason slow growing tumors may take months to regress completely. The damage suffered the deoxyribonucleic acid is not visible until the cell is in mitosis. this time deoxyribonucleic acid damage becomes manifested in the form of chromosomal aberrations, bizarre cell forms and, ultimately, cell death. Can a morphologist, even with the aid of a sophis-
433
Reply by Authors. We appreciate Doctors Pilepich and Stewart's editorial interest and incisive comments on our investigation into the effects of radiation on prostatic adenocarcinoma. As most investigators are well aware electron microscopy can only provide a static interpretation of a dynamic biological process and, therefore, has considerable limitations. The ability to distinguish malignant cells that are capable of further cell division from those that have been damaged irreversibly by radiation therapy and cannot complete mitosis is the fundamental issue. Doctors Pilepich and Stewart point to the 6 patients in whom we observed light and electron microscopic evidence of epithelial cells indistinguishable from untreated malignant cells and question whether we truly are observing cells with malignant potential (that is cells that are capable of further cell division). We agree with Doctors Pilepich and Stewart in that we cannot with absolute certainty verify om assumption that these cells retain a malignant potential. However, it is of interest that since submitting our manuscript for publication followup observations on 4 of these patients have shown clinical evidence of metastatic disease, with 1 death of prostatic metastases. It may well be that the tumors had metastasized before radiation therapy and we actually are observing the effects of untreated malignancy. As pointed out in our conclusion we are dealing in this study with a small group of patients and reliability of morphological criteria in establishing malignant potential of cells must await a larger sampling of patients and correlation with the clinical course of these patients. In addition, we currently are attempting to apply cell culturing techniques to irradiated and nonirradiated prostatic cancer tissue and correlating our findings with ultrastructural observations. Perhaps these studies may provide further useful information on the response of prostatic adenocarcinoma to radiation therapy.
0022-534 7/80/1242-0433$02.00/0
Printed in U.S.A.
THE ,JoURNAL OF UROLOGY
Copyright © 1980 by The Williams & Wilkins Co.
Letters to the Editor IDIOPATHIC RETROPEHITONEAL FIBROSIS
To the Editor. In the excellent review article by Lepor and Walsh the association of retroperitoneal fibrosis with other forms of sclerosing fibrosis, vasculitis and collagen vascular-like processes, for example Weber-Christian disease, was indicated and supported by a large number of individual case reports. 1 An additional possible association of retroperitoneal fibrosis with a vascular necrosis of the femoral head has been reported.'·" In these 2 case reports both patients were women and had femoral head necrosis on the same side as the respective unilateral retroperitoneal fibrosis, an entity that is reported as unilateral in only 25 per cent of the cases.4 In consideration of the possible relationship certain variables were excluded that are known to be associated with retroperitoneal fibrosis or femoral head necrosis, such as the use of methysergide or corticosteroids. Since the origin of both entities was undetermined one also must consider these 2 entities as possibly because of a generalized collagen disease, vasculitis, hypersensitivity state or autoimmune reaction. Respectfully, Rodney A. Appell Department of Urology Louisiana State University Medical Center New Orleans, Louisiana 70112
ticated electron microscope, detect at the time when the cells are not in mitosis morphological changes that will alter the cell's future reproductive capabilities? This appears to be a formidable task. The authors state that "of the 6 patients with definitive evidence of either recurrent or continued malignancy after radiation the ultrastructural appearance of the tumor was indistinguishable untreated carcinoma, suggesting that the tumor cells were still viable". The only definitive evidence of recurrent or continued malignancy can be, by definition, its regrowth. The authors also remark that totally benign-appearing epithelium was observed in patients with no evidence of tumor after irradiation. They cite this finding as evidence that there is regrowth of normal prostatic epithelium after the malignancy has been eradicated. This is hardly surprising since a certain degree of repopulation occurs normally in irradiated tissues. Indeed, differential recovery is one of the fundamental processes upon which radiation therapy is based, for it enables one to eradicate the tumor while preserving normal tissues." We must agree with Doctor Mostofi's editorial comment that morphological determination of tumor cell viability would be highly desirable but that electron microscopy appears to be of little value in achieving such a goal. Respectfully, Miljenko V. Pilepich and Carleton C. Stewart Division of Radiation Oncology Washington University School of Medicine St Louis, Missouri 63108
1. Lepor, H. and Walsh, P. C.: Idiopathic retroperitoneal fibrosis. J.
Urol., 122: 1, 1979. 2. n..,uuua1. B. A.: A vascular necrosis of the head of the femur in a case retroperitoneal fibrosis. Postgrad. Med. J., 49: 59, 1973. 3. Appell, R. A. and Weiss, R. M.: Retroperitoneal fibrosis and avascular necrosis of the femoral head. J.A.M.A., 236: 2886, 1976. 4. Watts, H. G.: Retroperitoneal fibrosis. New Zeal. Med. J., 79: 247, 1973.
1. Andrews, J. R.: Cell killing by ionizing radiation. The
mechanism of cell killing. In: The Radio biology of Human Radiotherapy. Philadelphia: W. B. Saunders Co., chapt. 2, p. 15, 1968. 2. Andrews, J. R.: Cell populations. In: The Radiobiology of Human Cancer Radiotherapy. Philadelphia: W. B. Saunders Co., chapt. 5, pp. 58-94, 1968.
RE: THE ULTRASTRUCTURAL CHANGES OF PROSTATE ADENOCARCINOMA FOLLOWING EXTERNAL BEAM RADIATION THERAPY V. J. Kiesling, H.
Friedman, J. W. McAninch, D. A. Nachtsheim and T. J. Nemeth J. Urol., 122: 633-636, 1979
To the Editor. One of the aims of the study by Kiesling and associates was to "develop a set ofultrastructural criteria that will aid the clinician and pathologist in the detection of active, recurrent or residual carcinoma after radiation therapy". We believe it appropriate to point out statements in this report reflecting misconceptions of basic tumor biology and radiation effects on tumor and normal tissues. To be truly useful the test (electron microscopy) must be able to distinguish clonogenic tumor cells after irradiation. Viability, in this context, implies the surviving cell's capacity to produce new clones of tumor cells and not simply the cell's ability to remain metabolically active as suggested in the authors' introduction. The fundamental target of radiation is the cell's genetic material, the deoxyribonucleic acid molecule. 1 By inducing alterations in the structure of the cell's deoxyribonucleic acid radiation deprives the cell of its reproductive capability. Thus, while cells may accumulate lethal damin any phase of the cell cycle it is most often expressed during Tumors with a low growth fraction (slow growing tumors) may take longer to regress because the cells are not cycling and, therefore, do not express the accumulated lethal damage. This is one reason slow growing tumors may take months to regress completely. The damage suffered the deoxyribonucleic acid is not visible until the cell is in mitosis. this time deoxyribonucleic acid damage becomes manifested in the form of chromosomal aberrations, bizarre cell forms and, ultimately, cell death. Can a morphologist, even with the aid of a sophis-
433
Reply by Authors. We appreciate Doctors Pilepich and Stewart's editorial interest and incisive comments on our investigation into the effects of radiation on prostatic adenocarcinoma. As most investigators are well aware electron microscopy can only provide a static interpretation of a dynamic biological process and, therefore, has considerable limitations. The ability to distinguish malignant cells that are capable of further cell division from those that have been damaged irreversibly by radiation therapy and cannot complete mitosis is the fundamental issue. Doctors Pilepich and Stewart point to the 6 patients in whom we observed light and electron microscopic evidence of epithelial cells indistinguishable from untreated malignant cells and question whether we truly are observing cells with malignant potential (that is cells that are capable of further cell division). We agree with Doctors Pilepich and Stewart in that we cannot with absolute certainty verify om assumption that these cells retain a malignant potential. However, it is of interest that since submitting our manuscript for publication followup observations on 4 of these patients have shown clinical evidence of metastatic disease, with 1 death of prostatic metastases. It may well be that the tumors had metastasized before radiation therapy and we actually are observing the effects of untreated malignancy. As pointed out in our conclusion we are dealing in this study with a small group of patients and reliability of morphological criteria in establishing malignant potential of cells must await a larger sampling of patients and correlation with the clinical course of these patients. In addition, we currently are attempting to apply cell culturing techniques to irradiated and nonirradiated prostatic cancer tissue and correlating our findings with ultrastructural observations. Perhaps these studies may provide further useful information on the response of prostatic adenocarcinoma to radiation therapy.