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Neuroendocrine cells of the prostate and neuroendocrine differentiation in prostatic carcinoma: a review of morphologic aspects
NEUROENDOCRINE CELLS OF THE PROSTATE AND NEUROENDOCRINE DIFFERENTIATION IN PROSTATIC CARCINOMA: A REVIEW OF MORPHOLOGIC ASPECTS P. ANTHONY DI SANT’AGNESE
ABSTRACT Neuroendocrine cells of the prostate are intraepithelial regulatory cells that secrete serotonin and a variety of peptide hormones. It is hypothesized that these cells regulate both growth and differentiation, as well as exocrine secretory activity through endocrine, paracrine, neurocrine, and lumenocrine mechanisms. Neuroendocrine differentiation in prostatic carcinoma occurs as pure neuroendocrine malignancies, such as small-cell carcinoma and carcinoid/carcinoid-like tumors, as well as focal neuroendocrine differentiation in a more conventional prostatic adenocarcinoma. Neuroendocrine differentiation in prostatic carcinoma may have diagnostic and prognostic significance. UROLOGY 51 (Suppl 5A): 121–124, 1998. © 1998, Elsevier Science Inc. All rights reserved.
T
he prostatic neuroendocrine cell, also known as an endocrine–paracrine or amine precursor uptake and decarboxylation (APUD) cell, is an intraepithelial regulatory cell (Fig. 1).1,2 This cell displays hybrid epithelial/neural/endocrine characteristics, has long dendritic processes with nervelike varicosities,1–3 and has open (apical processes extending to the glandular lumen) and closed subtypes.1–3 Ultrastructural analysis reveals a wide diversity of neurosecretory-type granules, suggesting a variety of different functional subtypes.4 The variety of different subtypes was further confirmed by the diversity of secretory products, including serotonin3,5,6 and a variety of peptides, such as the chromogranin family of peptides,7,8 the calcitonin family of peptides including calcitonin, katacalcin, and calcitonin gene-related peptide,9,10 a thyroidstimulating hormone-like peptide,11 alpha human chorionic gonadotropin-like peptide,12 bombesin/ gastrin-releasing peptide,9,13 somatostatin,14 and parathyroid hormone-related protein.15,16 Neuroendocrine cells have also been shown to lack expression of the androgen receptor17,18 and express calcitonin receptor,19 the latter in a subset of prostatic neuroendocrine cells including calcitonin-secreting cells (autocrine and paracrine regulation). In addition, immunoreactivity with polyFrom the Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, New York Reprint requests: P. Anthony di Sant’Agnese, M.D., University of Rochester, 601 Elmwood Avenue, Rochester, New York 14642 © 1998, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
clonal antibodies to epidermal growth factor receptor and C-erbB-2 has been demonstrated on subpopulations of prostatic neuroendocrine cells.20 Neuroendocrine cells of the prostate are part of a much larger neuroendocrine regulatory system (also referred to as the amine precursor uptake and decarboxylation [APUD] system, as described by Pearse21) that characterizes the biochemical characteristics of these cells. Betterknown elements of this regulatory system are neuroendocrine cells of the gastrointestinal tract, lung, thyroid (C cells), and pancreas (Islets of Langerhans).22–24 On the basis of the above-described morphology of the prostatic neuroendocrine cells and the known activity of their secretory products, as well as by analogy with other elements of the APUD system that have been much better studied, it is likely that neuroendocrine cells of the prostate regulate both growth and exocrine secretory activity. In addition, neuroendocrine cells may regulate each other. The long dendritic processes suggest a paracrine regulation of adjacent epithelial cells, and evidence demonstrating that these neuroendocrine cell processes often make contact with each other, as well as the presence of a calcitonin receptor on subsets of neuroendocrine cells, including calcitonin-secreting cells, suggests both paracrine and autocrine regulation of neuroendocrine cells by other neuroendocrine cells. Furthermore, rela0090-4295/98/$19.00 PII S0090-4295(98)00064-8 121
FIGURE 1. Normal prostate with a focus of neuroendocrine cells (chromogranin A immunostain).
tively high levels of several peptides found in the seminal fluid25–27 suggest the possibility of lumenocrine secretion and regulation of cells lining the male genital tract and, possibly, the female genital tract. Afferent neuroprocesses seen in association with prostatic neuroendocrine cells suggest there may also be a neurocrine regulation whereby neuroendocrine cell secretions influence sensory nerves that may then set up reflex regulation of wider areas of the prostate. Finally, paracrine secretions may influence adjacent stromal cells (stromal– epithelial interactions). In addition to regulating each other, it is likely that the open type of cell, which has long specialized microvilli on the intraluminal apical processes found by electron microscopy,4 is regulated by a receptosensory mechanism whereby these cells ‘‘taste’’ the luminal contents and then send signals back to regulate adjacent epithelial cell secretions, monitoring pH, secretory proteins, mucins, etc. NEUROENDOCRINE DIFFERENTIATION IN PROSTATE CANCER Neuroendocrine differentiation in prostatic carcinoma may take the form of a pure neuroendocrine tumor, that is, small-cell carcinoma of the prostate, that may or may not express a neuroendocrine phenotype (but in the majority of instances does)1,2,28 –30 or a carcinoid/carcinoid-like tumor that expresses extensive, if not complete neuroendocrine differentiation.1,2,31,32 Small-cell carcinomas and carcinoid/carcinoid-like tumors constitute a small percentage of prostatic malignancies, probably representing ,5% of all prostatic malignancies, even if composite tumors that 122
are conventional adenocarcinomas with foci of small-cell carcinoma or carcinoid/carcinoid-like tumors are included.1 The most common type of neuroendocrine differentiation seen in prostate malignancy is that of focal individual cell neuroendocrine differentiation in a conventional adenocarcinoma (Fig. 2).1,2,33,34 This process represents a caricature of normal differentiation pathways in the prostate with approximately 10% of conventional prostatic carcinomas at least focally expressing large numbers of neoplastic neuroendocrine cells. All, or virtually all, carcinomas appear to have at least focal neuroendocrine differentiation, although it often is quite minimal with just scattered cells. Overall, it would appear that the total number of neuroendocrine cells in carcinomas is less than the number in normal tissue, and prostatic intraepithelial neoplasias show intermediate levels of neuroendocrine cells between carcinoma and normal.35 Neuroendocrine differentiation in prostatic carcinoma cannot usually be appreciated without special stains for serotonin and various peptide hormones, except in those cases with neuroendocrine cells with very large secretory granules that appear eosinophilic and have erroneously been referred to as Paneth-like cells.36 –38 It is recommended that this terminology be dropped.39 The best general markers for neuroendocrine differentiation are chromogranin A and serotonin, which, when stained, together will mark the largest number of neoplastic neuroendocrine cells (this is true for normal cells as well).1,2,7 In some cases only selected peptide hormones are expressed by cells with neuroendocrine differentiation. ThereUROLOGY 51 (Supplement 5A), May 1998
FIGURE 2. Prostatic adenocarcinoma with focal neuroendocrine differentiation (serotonin immunostain).
fore, the true degree of neuroendocrine differentiation cannot be accurately assessed without a large panel of antibodies to a variety of neuroendocrine products, particularly those known to be expressed by the normal neuroendocrine cell. In some instances, ectopic hormone production has been described, including, among other products, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), leu-enkephalin and beta-endorphin.1 Serum levels of neuron-specific enolase, chromogranin A, and other peptide hormones have been described in conjunction with prostatic carcinoma with neuroendocrine differentiation and may have some value as a prognostic and diagnostic technique.40,41 The androgen receptor is not expressed by malignant neuroendocrine cells.17,18 There is evidence to suggest that neuroendocrine differentiation in conventional prostatic adenocarcinoma may have prognostic significance.1,2,7,42– 45 Others, however, have not found any prognostic significance.38,46,47 A discussion of prognostic significance is beyond the scope of this article, but is discussed by Abrahamsson in his review article in this Festschrift.48 REFERENCES 1. di Sant’Agnese P: Neuroendocrine differentiation in carcinoma of the prostate. Diagnostic, prognostic, and therapeutic implications. Cancer 70: 254 –268, 1992. 2. di Sant’Agnese P: Neuroendocrine differentiation in prostatic carcinoma. Recent findings and new concepts. Cancer 75: 1850 –1859, 1995. 3. di Sant’Agnese P, and de Mesy Jensen K: Human prostatic endocrine-paracrine (APUD) cells: distributional analysis with a comparison of serotonin and neuron-specific enolase immunoreactivity and silver stains. Arch Pathol Lab Med 109: 607– 612, 1985. UROLOGY 51 (Supplement 5A), May 1998
4. di Sant’Agnese P, and de Mesy Jensen K: Endocrine-paracrine cells of the prostate and prostatic urethra; an ultrastructural study. Hum Pathol 15: 1034 –1041, 1984. 5. Fetissof F, Dubois MP, and Arbeille-Brassart B, et al: Endocrine cells in the prostate gland, urothelium and Brenner tumors: immunohistological and ultrastructural studies. Virchows Arch 42: 53– 64, 1983. 6. Abrahamsson P-A, Wadstrom LB, and Alumets J, et al: Peptide hormone- and serotonin-immunoreactive cells in normal and hyperplastic prostate glands. Path Res Pract 181: 675– 683, 1986. 7. Abrahamsson P-A, Falkmer S, Falt K, and Grimelius L: The course of neuroendocrine differentiation in prostatic carcinomas: an immunohistochemical study testing chromogranin A as an ‘‘endocrine marker.’’ Pathol Res Pract 185: 373–380, 1989. 8. Schmid K, Helpap B, Totsch M, Kirchmair M, DockhornDworniczak B, and Bucker W, et al: Immunohistochemical localization of chromogranins A and B and secretogranin II in normal, hyperplastic and neoplastic prostate. Histopathology 24: 233–239, 1994. 9. di Sant’Agnese PA: Calcitonin-like immunoreactive and bombesin-like immunoreactive endocrine-paracrine cells of the human prostate. Arch Pathol Lab Med 110: 412– 415, 1986. 10. di Sant’Agnese P, and de Mesy Jensen K: Calcitonin, katacalcin and calcitonin gene-related peptide in the human prostate: an immunocytochemical and immunoelectron microscopic study. Arch Pathol Lab Med 113: 790 –796, 1989. 11. Abrahamsson P-A, and Lilja H: Partial characterization of a thyroid-stimulating hormone-like peptide in neuroendocrine cells of the human prostate gland. Prostate 14: 71– 81, 1989. 12. Fetissof F, Arbeille B, Guilloteau D, and Lanson Y: Glycoprotein hormone a-chain-immunoreactive endocrine cells in prostate and cloacal derived tissues. Arch Pathol Lab Med 111: 836 – 840, 1987. 13. Sunday M, Kaplan L, Motoyama E, Chin W, and Spindel E: Biology of disease. Gastrin-releasing peptide (mammalian bombesin) gene expression in health and disease. Lab Invest 59: 5–24, 1988. 14. di Sant’Agnese P, and de Mesy Jensen K: Somatostatin and/or somatostatin-like immunoreactive endocrine-para123
crine cells in the human prostate gland. Arch Pathol Lab Med 108: 693– 696, 1984. 15. Iwamura M, Wu G, Abrahamsson P-A, di Sant’Agnese P, Cockett A, and Deftos L: Parathyroid hormone-related protein is expressed by prostatic neuroendocrine cells. Urology 43: 667– 674, 1994. 16. Iwamura M, Wu G, Abrahamsson P-A, Cockett A, Foss K, and Deftos L: Parathyroid hormone-related protein: a potential autocrine growth regulator in human prostate cancer cell lines. Urology 43: 675– 679, 1994. 17. Bonkhoff H, Stein U, and Remberger K: Androgen receptor status in endocrine-paracrine cell types of the normal, hyperplastic, and neoplastic human prostate. Virchows Archiv A Pathol Anat Histopathol 423: 291–294, 1993. 18. Krijnen J, Janssen P, Ruizveld de Winter J, van Krimpen H, Schroder F, and van der Kwast T: Do neuroendocrine cells in human prostate cancer express androgen receptor? Histochemistry 100: 393–398, 1993. 19. Wu G, Burzon T, di Sant’Agnese P, Schoen S, Deftos L, Gershagen S, and Cockett A: Calcitonin receptor mRNA expression in the human prostate. Urology 47: 376 –381, 1996. 20. Iwamura M, Benning C, di Sant’Agnese P, Cockett A, Wu G, and Gershagen S: Overexpression of human epidermal growth factor receptor and c-erbB-2 by neuroendocrine cells in normal prostatic tissue. Urology 43: 838 – 843, 1994. 21. Pearse A: The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic, and pathologic implications of the concepts. J Histochem Cytochem 17: 303–313, 1969. 22. Larsson L-I: On the possible existence of multiple endocrine, paracrine and neurocrine messengers in secretory cell systems. Invest Cell Pathol 3: 73– 85, 1980. 23. Cutz E: Neuroendocrine cells of the lung: an overview of morphologic characteristics and development. Exp Lung Res 3: 185–208, 1982. 24. Bishop A, and Polak J: Gut endocrine and neural peptides. Endocr Pathol 1: 4 –24, 1990. 25. Sjoberg HE, Arver S, and Bucht E: High concentration of immunoreactive calcitonin of prostatic origin in human semen. Acta Physiol Scand 110: 101–102, 1980. 26. Ulisse S, Gnessi L, and Fabbri A, et al: Bombesin-like immunoreactivity in human seminal fluid. Regul Peptides 19: 143, 1987. 27. Sasaki A, and Yoshinaga K: Immunoreactive somatostatin in male reproductive system in humans. J Clin Endocrinol Metab 68: 996 –999, 1989. 28. Ro J, Tetu B, and Ayala A, et al: Small cell carcinoma of the prostate: immunohistochemical and electron microscopic studies of 18 cases. Cancer 59: 977–982, 1987. 29. Tetu B, Ro J, and Ayala A, et al: Small cell carcinoma of the prostate part I: a clinicopathologic study of 20 cases. Cancer 59: 1803–1809, 1987. 30. Abbas F, Civantos F, Benedetto P, and Soloway M: Small cell carcinoma of the bladder and prostate. Urology 46: 617– 630, 1995. 31. Almagro U, Tieu T, and Remeniuk E, et al: Argyrophilic, ‘carcinoid-like’ prostatic carcinoma. Arch Pathol Lab Med 110: 916 –919, 1986.
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32. Stratton M, Evans D, and Lambert I: Prostatic adenocarcinoma evolving into carcinoid: selective effect of hormonal treatment? J Clin Pathol 39: 750 –756, 1986. 33. Abrahamsson P-A, Wadstrom L, and Alumets J, et al: Peptide hormone- and serotonin-immunoreactive tumour cells in carcinoma of the prostate. Path Res Pract 182: 298 – 307, 1987. 34. di Sant’Agnese P, and de Mesy Jensen K: Neuroendocrine differentiation in prostatic carcinoma. Human Pathology 18: 849 – 856, 1987. 35. Algaba F, Trias I, Lopez L, Rodriguez-Vallejo J, and Gonzalez-Esteban J: Neuroendocrine cells in peripheral prostatic zone: age, prostatic intraepithelial neoplasia and latent cancer-related changes. Eur Urol 27: 329 –333, 1995. 36. Weaver M, Abdul-Karim F, Srigley J, Bostwick D, Ro J, and Ayala A: Paneth cell-like change of the prostate gland. A histological, immunohistochemical, and electron microscopic study. Am J Surg Pathol 16: 62– 68, 1992. 37. Van de Voorde W, Van Poppel H, Haustermans K, Baert L, and Lauweryns J: Mucin-secreting adenocarcinoma of the prostate with neuroendocrine differentiation and Paneth-like cells. Am J Surg Pathol 18: 200 –207, 1994. 38. Adlakha H, and Bostwick D: Paneth cell-like change in prostatic adenocarcinoma represents neuroendocrine differentiation. Report of 30 cases. Hum Pathol 25: 135–139, 1994. 39. di Sant’Agnese P: Neuroendocrine differentiation in prostatic adenocarcinoma does not represent true Paneth cell differentiation. Human Pathol 25: 115–116, 1994. 40. Tarle M, and Rados N: Investigation on serum neuronespecific enolase in prostate cancer diagnosis and monitoring: comparative study of a multiple tumor marker assay. Prostate 19: 23, 1991. 41. Kadmon D, Thompson T, Lynch G, and Scardino P: Elevated plasma chromogranin-A concentrations in prostatic carcinoma. J Urol 146: 358 –361, 1991. 42. Cohen R, Glezerson G, Haffejee Z, and Africa D: Prostatic carcinoma: histological and immunohistological factors affecting prognosis. Br J Urol 66: 405– 410, 1990. 43. Berner A, Nesland J, Waehre H, Slide J, and Fossa S: Hormone resistant prostatic adenocarcinoma. An elevation of prognostic factors in pre- and post-treatment specimens. Br J Cancer 68: 380 –384, 1993. 44. Weinstein M, Partin A, Veltri R, and Epstein J: Neuroendocrine differentiation in prostate cancer: enhanced prediction of progression after radical prostatectomy. Hum Pathol 27: 683– 687, 1996. 45. Grignon D, Caplan R, Sakr W, Porter A, Doggen R, John M, Abrams R, and Lawton C: Neuroendocrine (NE) differentiation as a prognostic indicator in locally advanced prostate cancer (PCa). Lab Invest 72: 76A, 1995. 46. Aprikian A, Cordon-Cardo C, Fan W, and Reuter V: Characterization of neuroendocrine differentiation in human benign prostate and prostatic adenocarcinoma. Cancer 71: 3952–3965, 1993. 47. Allen F, VanVelden D, Heyns: Are neuroendocrine cells of practical value as an independent prognostic parameter in prostate cancer? Br J Urol 75: 751–754, 1995.
UROLOGY 51 (Supplement 5A), May 1998
ABSTRACT Neuroendocrine cells of the prostate are intraepithelial regulatory cells that secrete serotonin and a variety of peptide hormones. It is hypothesized that these cells regulate both growth and differentiation, as well as exocrine secretory activity through endocrine, paracrine, neurocrine, and lumenocrine mechanisms. Neuroendocrine differentiation in prostatic carcinoma occurs as pure neuroendocrine malignancies, such as small-cell carcinoma and carcinoid/carcinoid-like tumors, as well as focal neuroendocrine differentiation in a more conventional prostatic adenocarcinoma. Neuroendocrine differentiation in prostatic carcinoma may have diagnostic and prognostic significance. UROLOGY 51 (Suppl 5A): 121–124, 1998. © 1998, Elsevier Science Inc. All rights reserved.
T
he prostatic neuroendocrine cell, also known as an endocrine–paracrine or amine precursor uptake and decarboxylation (APUD) cell, is an intraepithelial regulatory cell (Fig. 1).1,2 This cell displays hybrid epithelial/neural/endocrine characteristics, has long dendritic processes with nervelike varicosities,1–3 and has open (apical processes extending to the glandular lumen) and closed subtypes.1–3 Ultrastructural analysis reveals a wide diversity of neurosecretory-type granules, suggesting a variety of different functional subtypes.4 The variety of different subtypes was further confirmed by the diversity of secretory products, including serotonin3,5,6 and a variety of peptides, such as the chromogranin family of peptides,7,8 the calcitonin family of peptides including calcitonin, katacalcin, and calcitonin gene-related peptide,9,10 a thyroidstimulating hormone-like peptide,11 alpha human chorionic gonadotropin-like peptide,12 bombesin/ gastrin-releasing peptide,9,13 somatostatin,14 and parathyroid hormone-related protein.15,16 Neuroendocrine cells have also been shown to lack expression of the androgen receptor17,18 and express calcitonin receptor,19 the latter in a subset of prostatic neuroendocrine cells including calcitonin-secreting cells (autocrine and paracrine regulation). In addition, immunoreactivity with polyFrom the Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, New York Reprint requests: P. Anthony di Sant’Agnese, M.D., University of Rochester, 601 Elmwood Avenue, Rochester, New York 14642 © 1998, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
clonal antibodies to epidermal growth factor receptor and C-erbB-2 has been demonstrated on subpopulations of prostatic neuroendocrine cells.20 Neuroendocrine cells of the prostate are part of a much larger neuroendocrine regulatory system (also referred to as the amine precursor uptake and decarboxylation [APUD] system, as described by Pearse21) that characterizes the biochemical characteristics of these cells. Betterknown elements of this regulatory system are neuroendocrine cells of the gastrointestinal tract, lung, thyroid (C cells), and pancreas (Islets of Langerhans).22–24 On the basis of the above-described morphology of the prostatic neuroendocrine cells and the known activity of their secretory products, as well as by analogy with other elements of the APUD system that have been much better studied, it is likely that neuroendocrine cells of the prostate regulate both growth and exocrine secretory activity. In addition, neuroendocrine cells may regulate each other. The long dendritic processes suggest a paracrine regulation of adjacent epithelial cells, and evidence demonstrating that these neuroendocrine cell processes often make contact with each other, as well as the presence of a calcitonin receptor on subsets of neuroendocrine cells, including calcitonin-secreting cells, suggests both paracrine and autocrine regulation of neuroendocrine cells by other neuroendocrine cells. Furthermore, rela0090-4295/98/$19.00 PII S0090-4295(98)00064-8 121
FIGURE 1. Normal prostate with a focus of neuroendocrine cells (chromogranin A immunostain).
tively high levels of several peptides found in the seminal fluid25–27 suggest the possibility of lumenocrine secretion and regulation of cells lining the male genital tract and, possibly, the female genital tract. Afferent neuroprocesses seen in association with prostatic neuroendocrine cells suggest there may also be a neurocrine regulation whereby neuroendocrine cell secretions influence sensory nerves that may then set up reflex regulation of wider areas of the prostate. Finally, paracrine secretions may influence adjacent stromal cells (stromal– epithelial interactions). In addition to regulating each other, it is likely that the open type of cell, which has long specialized microvilli on the intraluminal apical processes found by electron microscopy,4 is regulated by a receptosensory mechanism whereby these cells ‘‘taste’’ the luminal contents and then send signals back to regulate adjacent epithelial cell secretions, monitoring pH, secretory proteins, mucins, etc. NEUROENDOCRINE DIFFERENTIATION IN PROSTATE CANCER Neuroendocrine differentiation in prostatic carcinoma may take the form of a pure neuroendocrine tumor, that is, small-cell carcinoma of the prostate, that may or may not express a neuroendocrine phenotype (but in the majority of instances does)1,2,28 –30 or a carcinoid/carcinoid-like tumor that expresses extensive, if not complete neuroendocrine differentiation.1,2,31,32 Small-cell carcinomas and carcinoid/carcinoid-like tumors constitute a small percentage of prostatic malignancies, probably representing ,5% of all prostatic malignancies, even if composite tumors that 122
are conventional adenocarcinomas with foci of small-cell carcinoma or carcinoid/carcinoid-like tumors are included.1 The most common type of neuroendocrine differentiation seen in prostate malignancy is that of focal individual cell neuroendocrine differentiation in a conventional adenocarcinoma (Fig. 2).1,2,33,34 This process represents a caricature of normal differentiation pathways in the prostate with approximately 10% of conventional prostatic carcinomas at least focally expressing large numbers of neoplastic neuroendocrine cells. All, or virtually all, carcinomas appear to have at least focal neuroendocrine differentiation, although it often is quite minimal with just scattered cells. Overall, it would appear that the total number of neuroendocrine cells in carcinomas is less than the number in normal tissue, and prostatic intraepithelial neoplasias show intermediate levels of neuroendocrine cells between carcinoma and normal.35 Neuroendocrine differentiation in prostatic carcinoma cannot usually be appreciated without special stains for serotonin and various peptide hormones, except in those cases with neuroendocrine cells with very large secretory granules that appear eosinophilic and have erroneously been referred to as Paneth-like cells.36 –38 It is recommended that this terminology be dropped.39 The best general markers for neuroendocrine differentiation are chromogranin A and serotonin, which, when stained, together will mark the largest number of neoplastic neuroendocrine cells (this is true for normal cells as well).1,2,7 In some cases only selected peptide hormones are expressed by cells with neuroendocrine differentiation. ThereUROLOGY 51 (Supplement 5A), May 1998
FIGURE 2. Prostatic adenocarcinoma with focal neuroendocrine differentiation (serotonin immunostain).
fore, the true degree of neuroendocrine differentiation cannot be accurately assessed without a large panel of antibodies to a variety of neuroendocrine products, particularly those known to be expressed by the normal neuroendocrine cell. In some instances, ectopic hormone production has been described, including, among other products, adrenocorticotropic hormone (ACTH), antidiuretic hormone (ADH), leu-enkephalin and beta-endorphin.1 Serum levels of neuron-specific enolase, chromogranin A, and other peptide hormones have been described in conjunction with prostatic carcinoma with neuroendocrine differentiation and may have some value as a prognostic and diagnostic technique.40,41 The androgen receptor is not expressed by malignant neuroendocrine cells.17,18 There is evidence to suggest that neuroendocrine differentiation in conventional prostatic adenocarcinoma may have prognostic significance.1,2,7,42– 45 Others, however, have not found any prognostic significance.38,46,47 A discussion of prognostic significance is beyond the scope of this article, but is discussed by Abrahamsson in his review article in this Festschrift.48 REFERENCES 1. di Sant’Agnese P: Neuroendocrine differentiation in carcinoma of the prostate. Diagnostic, prognostic, and therapeutic implications. Cancer 70: 254 –268, 1992. 2. di Sant’Agnese P: Neuroendocrine differentiation in prostatic carcinoma. Recent findings and new concepts. Cancer 75: 1850 –1859, 1995. 3. di Sant’Agnese P, and de Mesy Jensen K: Human prostatic endocrine-paracrine (APUD) cells: distributional analysis with a comparison of serotonin and neuron-specific enolase immunoreactivity and silver stains. Arch Pathol Lab Med 109: 607– 612, 1985. UROLOGY 51 (Supplement 5A), May 1998
4. di Sant’Agnese P, and de Mesy Jensen K: Endocrine-paracrine cells of the prostate and prostatic urethra; an ultrastructural study. Hum Pathol 15: 1034 –1041, 1984. 5. Fetissof F, Dubois MP, and Arbeille-Brassart B, et al: Endocrine cells in the prostate gland, urothelium and Brenner tumors: immunohistological and ultrastructural studies. Virchows Arch 42: 53– 64, 1983. 6. Abrahamsson P-A, Wadstrom LB, and Alumets J, et al: Peptide hormone- and serotonin-immunoreactive cells in normal and hyperplastic prostate glands. Path Res Pract 181: 675– 683, 1986. 7. Abrahamsson P-A, Falkmer S, Falt K, and Grimelius L: The course of neuroendocrine differentiation in prostatic carcinomas: an immunohistochemical study testing chromogranin A as an ‘‘endocrine marker.’’ Pathol Res Pract 185: 373–380, 1989. 8. Schmid K, Helpap B, Totsch M, Kirchmair M, DockhornDworniczak B, and Bucker W, et al: Immunohistochemical localization of chromogranins A and B and secretogranin II in normal, hyperplastic and neoplastic prostate. Histopathology 24: 233–239, 1994. 9. di Sant’Agnese PA: Calcitonin-like immunoreactive and bombesin-like immunoreactive endocrine-paracrine cells of the human prostate. Arch Pathol Lab Med 110: 412– 415, 1986. 10. di Sant’Agnese P, and de Mesy Jensen K: Calcitonin, katacalcin and calcitonin gene-related peptide in the human prostate: an immunocytochemical and immunoelectron microscopic study. Arch Pathol Lab Med 113: 790 –796, 1989. 11. Abrahamsson P-A, and Lilja H: Partial characterization of a thyroid-stimulating hormone-like peptide in neuroendocrine cells of the human prostate gland. Prostate 14: 71– 81, 1989. 12. Fetissof F, Arbeille B, Guilloteau D, and Lanson Y: Glycoprotein hormone a-chain-immunoreactive endocrine cells in prostate and cloacal derived tissues. Arch Pathol Lab Med 111: 836 – 840, 1987. 13. Sunday M, Kaplan L, Motoyama E, Chin W, and Spindel E: Biology of disease. Gastrin-releasing peptide (mammalian bombesin) gene expression in health and disease. Lab Invest 59: 5–24, 1988. 14. di Sant’Agnese P, and de Mesy Jensen K: Somatostatin and/or somatostatin-like immunoreactive endocrine-para123
crine cells in the human prostate gland. Arch Pathol Lab Med 108: 693– 696, 1984. 15. Iwamura M, Wu G, Abrahamsson P-A, di Sant’Agnese P, Cockett A, and Deftos L: Parathyroid hormone-related protein is expressed by prostatic neuroendocrine cells. Urology 43: 667– 674, 1994. 16. Iwamura M, Wu G, Abrahamsson P-A, Cockett A, Foss K, and Deftos L: Parathyroid hormone-related protein: a potential autocrine growth regulator in human prostate cancer cell lines. Urology 43: 675– 679, 1994. 17. Bonkhoff H, Stein U, and Remberger K: Androgen receptor status in endocrine-paracrine cell types of the normal, hyperplastic, and neoplastic human prostate. Virchows Archiv A Pathol Anat Histopathol 423: 291–294, 1993. 18. Krijnen J, Janssen P, Ruizveld de Winter J, van Krimpen H, Schroder F, and van der Kwast T: Do neuroendocrine cells in human prostate cancer express androgen receptor? Histochemistry 100: 393–398, 1993. 19. Wu G, Burzon T, di Sant’Agnese P, Schoen S, Deftos L, Gershagen S, and Cockett A: Calcitonin receptor mRNA expression in the human prostate. Urology 47: 376 –381, 1996. 20. Iwamura M, Benning C, di Sant’Agnese P, Cockett A, Wu G, and Gershagen S: Overexpression of human epidermal growth factor receptor and c-erbB-2 by neuroendocrine cells in normal prostatic tissue. Urology 43: 838 – 843, 1994. 21. Pearse A: The cytochemistry and ultrastructure of polypeptide hormone-producing cells of the APUD series and the embryologic, physiologic, and pathologic implications of the concepts. J Histochem Cytochem 17: 303–313, 1969. 22. Larsson L-I: On the possible existence of multiple endocrine, paracrine and neurocrine messengers in secretory cell systems. Invest Cell Pathol 3: 73– 85, 1980. 23. Cutz E: Neuroendocrine cells of the lung: an overview of morphologic characteristics and development. Exp Lung Res 3: 185–208, 1982. 24. Bishop A, and Polak J: Gut endocrine and neural peptides. Endocr Pathol 1: 4 –24, 1990. 25. Sjoberg HE, Arver S, and Bucht E: High concentration of immunoreactive calcitonin of prostatic origin in human semen. Acta Physiol Scand 110: 101–102, 1980. 26. Ulisse S, Gnessi L, and Fabbri A, et al: Bombesin-like immunoreactivity in human seminal fluid. Regul Peptides 19: 143, 1987. 27. Sasaki A, and Yoshinaga K: Immunoreactive somatostatin in male reproductive system in humans. J Clin Endocrinol Metab 68: 996 –999, 1989. 28. Ro J, Tetu B, and Ayala A, et al: Small cell carcinoma of the prostate: immunohistochemical and electron microscopic studies of 18 cases. Cancer 59: 977–982, 1987. 29. Tetu B, Ro J, and Ayala A, et al: Small cell carcinoma of the prostate part I: a clinicopathologic study of 20 cases. Cancer 59: 1803–1809, 1987. 30. Abbas F, Civantos F, Benedetto P, and Soloway M: Small cell carcinoma of the bladder and prostate. Urology 46: 617– 630, 1995. 31. Almagro U, Tieu T, and Remeniuk E, et al: Argyrophilic, ‘carcinoid-like’ prostatic carcinoma. Arch Pathol Lab Med 110: 916 –919, 1986.
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UROLOGY 51 (Supplement 5A), May 1998