Neuroendocrine Differentiation in Human Prostatic Carcinoma P. ANTHONY

DI SANT’AGNESE,

MD

Endocrine-paracrine (APUD. neuroendocrine) cells are located in the prostatic ductal and acinar epithelium. These cells are of the open and closed type and have dendritic processes. There is a wide range of secretory granule morphology presumably indicating a variety of different cell “types.” Secretory immunoreactive peptides include serotonin, calcitonin (and related peptides), somatostatin, bombesin-like, thyroid-stimulating hormone-like (beta chain), and alpha-glycoprotein chain-like. These cells may function by endocrine, paracrine, neurocrine, and lumencrine mechanisms and play an important regulatory role both during growth and differentiation of the prostate as well as in the secretory process of the mature gland. Neuroendocrine differentiation in prostatic carcinoma is a frequent occurrence and manifests itself in several forms, including (I) small cell carcinoma, (2) carcinoid and carcinoid-like tumors, and (3) conventional adenocarcinoma with focal neuroendocrine differentiation. This latter pattern is the most common, and there is evidence that all or nearly all prostatic adenocarcinomas show at least some focal neuroendocrine differentiation. A review of the world’s literature on this topic is included. Neuroendocrine differentiation generally portends a poorer prognosis but may also correlate directly with the grade. There is some evidence to suggest that neoplastic cells with neuroendocrine differentiation are resistant to hormonal therapy. Eutopic and ectopic hormone production may allow screening for prostatic carcinoma and/or monitoring for recurreoce of prostatic carcinomas. Finally, the more basic implications of endocrine-paracrine cells and neuroendocrine differentiation are speculated on in reference to prostatic carcinogenesis and autocrine/paracrine tumor growth factor activity. HUM PATHOL 23:287-296. Copyright cc31 1992 by W.B. Saunders Company

In this review the prostatic endocrine-paracrine cell and known secretory products will be described in a historic context with speculation on the possible functional role these cells may play. With this background in mind, the evidence for neuroendocrine differentiation in prostatic malignancy will be presented together with a review of the world’s literature. Finally, the clinical as well as more basic implications will be discussed. ENDOCRINE-PARACRINE OF THE PROSTATE

Endocrine-paracrine cells (also known as neuroentlorrine or APUD cells) were first described in the prostatourethral region by Pretl in 1944.’ Since that time, 1)rostatic endocrine-paracrine cells have become recognized as indigenous to the normal prostatic epithelium a’s ;I third epithelial cell type along with the secretory and basal cells.“-” I,ittle is known of the functional role these cmdocrine-paracrine cells may play in the prostate. Their ~norpholo~~ and secretory products, along with their similarity to the more extensively investigated endocrine-par;tcrine cells of the gastroenteropancreatic and pulmonary kystenis. suggest they serve an important regulatory role both dutilng growth and differentiation as well ac in the secretory process of the mature gland.’ Neoplastic endocrineparacl-ine cells play an important role in the pathologic prostate. Neuroendocrine carcinoma and focal neuroenclocrine differentiation in conventional prostatic ;tdenocarcinoma are relatively frequent occurrences with 1)otentiallv significant clinical implications.‘-’ ’

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Endocrine-paracrine cells have been reported in a variety of sites in the male and female genitourinary tracts. They are relatively abundant in the male”,‘” and female’g,“’ urethra with a much smaller number of cells reported in the bladder, renal pelvis, and ureter’” as well as in the female genital tract.‘” The prostate, however, contains the largest number of endocrine-paracrine cells of any genitourinary organ, male or female. Prostatic endocrine-paracrine cells (Figs 1 to 5) are irregularly distributed throughout the ducts and acini with a larger number generally found in the duct system.‘.” The number of cells varies considerably from individual to individual. Endocrine-paracrine cells are morphologically of the open and closed type and frequently display long dendritic processes extending under or between adjacent epithelial cells.“,” Open cell types have long apical cytoplasmic processes extending to the lumen with long specialized microvilli on the apical surface protruding into the lumenal secretion. Ultrastructural study of prostatic endocrine-paracrine cells has shown a wide array of secretory granule morphology varying considerably from cell to cell as well as within individual cells. There appear to be a wide variety of at least as related to secretory granule cell “types,” morphology:. There is evidence of’ innervation of prostatic endocrine-paracrine cells by both afferent and efferent nerves.” Most endocrine-paracrine cells of the prostate contain immunoreactive serotonin. which is present in the and is, therefore, presumably a scsecretory granules” cretory product. Levels of prostatic serotonin have been analyzed quantitatively’” and are comparable to those found in those portions of the gastrointestinal tract and brain containing the highest levels. Levels of serotonin found in the normal human prostate were 1.42 pg/g I 0.75 (N = X). Other peptides also described in subpopulations of prostatic endocrine-paracrine cells include ca]citonin,“‘,?l gene-related peptide,‘” katacalcin.” bombesin-like (probably the mammalian peptide gastrinreleasing peptide),“” somatostatin,” alpha-human chorionic gonadotrophin,‘” and thyroid-stimulating hormone-like.“,‘?” Several of these peptides have been detected in high levels in the semen, including calcitonin,

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FIGURE 1. Serotonin-immunoreactive endocrine-paracrine cells demonstrating open and closed endocrine-paracrine cell types. (Serotonin immunoperoxidase; magnification x274.) (Reprinted with permission.53)

bombesin, and somatostatin. The thyroid-stimulating hormone-like peptide shows partial cross-reactivity with the thyroid-stimulating hormone beta chain but is not identical to the beta chain. 24 Calcitonin appears to be a true secretory product as it has been co-localized along with serotonin to the secretory granules.” There is strong evidence that true calcitonin is present in the prostate since two other products of the calcitonin gene (calcitonin gene-related peptide and katacalcin [a C-terminal flanking peptide in pro-calcitonin]) are co-expressed in subpopulations of calcitonin-immunoreactive cells.18 Furthermore, calcitonin has been measured in

the normal human prostate gland by radioimmunoassay and the dilution curves appear identical to monomeric calcitonin.25 In this study, levels of calcitonin were 15.8 rig/g f 10.0 (N = 20). In some prostates the level of calcitonin approached the order of magnitude found in the thyroid gland. Virtually nothing is known concerning the functional role endocrine-paracrine cells play in the normal or neoplastic prostate. Based on their morphology as well as their secretory products and, by analogy with the better-studied endocrine-paracrine cells of the gastroenteropancreatic and pulmonary systems,’ it is at-

FIGURE 2. Prostatic glands with several calcitonin immunoreactive endocrine-paracrine cells. (Calcitonin immunoperoxidase; magnification x274.) (Reprinted with permission.53)

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FIGURE 3. Three closedtype endocrine-parocrine cells of the prostate with contiguous borders. The two cells on the outside have rather large pleomorphic secretory granules and the cell in the middle has medium-sized pleomorphic secretory granules. (Magnification X6.156.) (Reprinted with permission.“3)

tractive to speculate that these cells play an important central role in the regulation of the gland. The prostatic endocrine-paracrine cells may regulate through autocrine, paracrine, endocrine, lumencrine, and neurocrine mechanisms. The morphology of the open-type cell suggests that the long apical microvilli contain receptors

that sense through physical and chemical signals the state of the lumenal contents and then homeostatically regulate secretion. This may occur in a paracrine manner by the release of serotonin and peptides via the dendritic processes to regulate adjacent cells. Homeostatir regulation may also occur on a wider local or systemic level

FIGURE 4. An open-type endocrine-paracrine cell with a long apical process extending to the lumen with specialized microvilli. Note the small pleomorphic granules primarily at the base of the cell. (Magnification with (Reprinted k 1,863.) permission.‘7)

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FIGURE 5. Granules present in the various cell “types”: a, PR 1; b, PR 2; c, PR 3: d, PR 4: e, PR 5; f, PR 6: g, PR 7; h, PR 8; and i, PR 9. (Magnification x25.000.) (Reprinted with permission.“)

epithelium and their contact with adjacent epithelial cells, the endocrine-paracrine cells may play a role in coordinating and directing stromal/epithelial cross-talk.

via endocrine or neurocrine mechanisms (in the latter, afferent nerves sending signals back to the nervous system, which then through reflex efferent autonomic signals regulates the glandular secretions). The high level of several endocrine-paracrine peptide products in semen suggests that they may play a regulatory role via the semen (lumencrine secretion), possibly targeting cells lining the prostatic acini and ducts as well as spermatozoa and cells of the female genital tract. Endocrine-paracrine cells also may have a central role during growth and differentiation of the prostate, a process that appears to be mediated by stromal/epithelial interaction.” Such a role has been attributed to endocrine-paracrine cells of the lung. Serotonin’” and several of the pe tides produced by prostatic endocrineP paracrine cells ‘.-’ are known to have trophic/growth factor-like actions. Given their central location in the

NEUROENDOCRINE DIFFERENTIATION HUMAN PROSTATIC CARCINOMA

IN

Neuroendocrine malignancies occur in a variety of sites in the male and female genitourinary systems. Carcinoid tumors have been described in the urethra,“’ bladder,‘” kidney, testes, ovary, and cervix. Small cell neuroendocrine carcinomas occur in the bladder”’ and rarely in the kidney, cervix, and endometrium. Carcinomas with focal neuroendocrine differentiation have been noted in several sites in the female genital tract.‘” It is likely that some neuroendocrine malignancies of

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FIGURE 6. Small cell carcinoma of the prostate with focal areas showing calcitonin immunoreactive cells. (Calcitonin immunoperoxidase; magnification X274.) (Reprinted with permission.53)

differentiation. Two hundred sixty-four cases are documented. Criteria for inclusion within Table 1 include (1) histologic patterns frequently associated with neuroendocrine differentiation, ie, small cell carcinoma (Fig 6) and carcinoid tumor with or without other evidence of neuroendocrine differentiation; (2) composite tumors with conventional adenocarcinoma combined with small cell carcinoma or carcinoid tumor; (3) conventional adenocarc,inonl;~s with focal neuroendocrine differentia-

the testes and ovary occur in association with teratomas. The prostate harbors by far the largest number of malignancies with neuroendocrine differentiation found in any organ of the male and female genitourinary tracts.” This is most likely a reflection of the fact that endocrineparacrine cells are found in the greatest abundance in the prostate among all genitourinary organs. Table 1 is a review of the world’s literature in reference to prostatic malignancies with neuroet IIII )or) WA+ WA, PAP-; 110 gra”u1.z EM Carrinoid PAP+

hy

cell Bouin’s fixative few

ACTH (8), CAL (?), betaendorphi” (3), GLUC (1). alpha-H% (11). Leu-ENK (8). SER (40) SOM (12), TSH (34) (ICC)

few

Adenocarcinoid Adenocarcinoma 6 Small cell; 5 adenocarcinoma/small cell; 9 adenocarcinoma + small cell

Poor response to endocrine therapy: increasing NE differentiation; poorer prognosis BOM (I), CAL (2). SER (10). ICC ACTH, BOM, CAL, GLUC. PTH, SOM. SER. ICC Beta-HCG (ICC)

Carcinoid

PSA and PAP

Poor response to endocl-ine therapy small cell; 15 PSA and PAP-; 3 PSA and PAP+ kall3 NSE-1

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TABLE 1.

(Continued

(P, Anthony di Sant’Agnese)

)

Abbwviatiuns: A(:TH, adrenocorticotrophic hormone; ADH. antidiuretic hormone; HCC. human chorionic gonadotrophin; CAL. cakitomn t ZRF‘.corttiotrophitI homm~mc: PSA, prostaticrelrasmg factor; GLUC, glucagon: ENK. enkephalin; PTH, parathormone: SER. serotonin; SOM, SomatoFtatin: TSH, thy roid-stimulating .\perlhc antigen; HIAA. hydroxindole acetic acid; BOM. homhesin: (:RH, corticotrophin-releasi~~g~~~~r~~~o~~e: EM, electron micnwopy; NSF, neur,m-spec ific cnolase. PAP. prostatic acid phosplratase: NE, neuroendocrine; ICC, immunocytochemist~ * Unless ICC is Indicated quantitative analysis was done. Swuhi M. J (:lin N? R. et al. Cancer 10:773. 1977. “Mollancl EA. B J Ilrol 50:358. 1978; PMontasser AY. Ong MC. Mehta VT: Cancer 44307, 1979: Wasserstein PW. Goldman RI.: I:rolohy X.318. 1!)79; ‘Miki T. Kuroda M. Kivohara H, et al: Jpn J Ural 71:264, 1980; ‘Papapetrou RD. Sakarelou NP. Braouzi H, t? al: Cancer 452583. 1980; ‘nsari M.4. Pintozri RI.. Choi YS, et al: Am Jr i;lin Pathol 76:94, 1981; “Vuitch MF, Mrndelsohn G: Cancer 47.296. 1981: Wasserstein PW. Goldman RL, LJrology 18:407. 19X1: “Ncmeth :I. Hcung C. Rawan P. ct al: Now Presse Med 2:605. 1982; ‘Samsonova VA: Arkh Patol 44:60. 1982: “Fukutani K. Lihhy JM. Pankn WB, et al:J Clwl 129:74, 19X.3; ‘hiahadevia PS Ramawamy A, Cl-eenwald ES, et al: Arch Intern Med 143:1339, 1983; “Carey RM. Varma SK, Drake CR, et al: N Engl J Med 31 I: IS. 1984; MJoss R. Jungi WF, K.apanu Y. et al: Schweir Med Wochenschr lI4:161. 1984: “Purnell DM. Heatfield BM. Trump BF. Cancer Res ‘44:285. 1984; ddAlmagro ITA. Canwr 55-608, 19X5; “Bono AV. Pozzi E: Eur Ural 2:195, 1985; “Dauge MC, Grossin M, Doumecq-Lacostr JM. et al: Arch .4nat Cytol Pathol 39:73. 1985. “Hindson DN: B J I’rol DA, Knight 1.1.. Ocker JM. Urology 26:1982. 1985; MPatel S. Rosenthal JT: Urology 25:627. 1985; “Sa&onova VA: Arkh Patol 47.7 2. 1!#5:“Slater 57:591, 1985; %nith CS: J Ural 133:37lA. 1985; “Almagro UA. Tieu TM, Remenuik E. et al- .4rch Pathol Lab Med 110:!~16. 1986; ““Frlissof F. Bruandet P. i\rhrille 8, et al. Am J Surg Pathol 10:702. 1986; ““Dauge MC, Delmas V: Progress in (tlinical and Biologtcal Mrdieine. New York, NY, I.iss, i!lX?. p 529: mRojasC~,rona RR, Chen I., Mahadevia PS: Am J Clin Pathol 88:759, 1987; “Shah VM. N ewman J, Crockel-J, et al: Br.1 Exp Pathol 68:871, 19X7; WI-vtu B, Ro JY. Ayala A(:, ct al: Cancu 59:1803. 1987; “Fjellestad-Paulsen A, Abrahamsson PA. Bjartell A, et al: Acta Endowinol (Copenh) ll9:5Oti. 198X; “Murao ‘I , I‘anahasht T: Jpn J (.ancer Clin 34: 1624, 19X8; “Turbat-Herrera EA, Herrera CA, Core I, et al: Arch Pathol I.ab Med I I ?: I 100, 1988; ““Abraharnsson PA, Falkrner S. Fait K, et al. 0 New York. NY. Fwd X- Wood Publisher\. 1WO. I’athol Res Prxt 185.373. 1989: ““di Sant’Agnese PA: Progrrs~ in Reproductive and IlrinaryTra0 Pathcplogv, vol _.

1’x7 Modified

with pet mission ‘“’

tion in a tumor that demonstrated a histologic and/or staining pattern consistent with carcinoid tumor. Prostate-specific antigen and prostatic acid phosphatase were positive in some cases with neuroendocrine differentiation32.3” and negative in others. “‘w” Adenocarcinoma with focal neuroendocrine differentiation was by far the most common pattern described in the literature (Fig 7). This most likely mirrors the normal differentiation process in prostatic epithelium whereby endocrine-paracrine cells along with basal and secretory cells differentiate from a common precursor cell. The concept of multidirectional differentiation in malignant neoplasms differenis now widely accepted. 38,39 Neuroendocrine tiation can occur in virtually any neoplasm, but is particularly common in malignancies arising from organs that contain a normal complement of endocrine-paracrine cells. The percentage of adenocarcinomas with detected focal neuroendocrine differentiation has progressively increased as the methods of detection have become more sensitive. In 197 1, Azzopardi and Evans” found five of 50 (10%) randomly studied prostatic carcinomas containing argentaffin-positive cells. In 1974 Kazzaz’” found eight of 50 (16%) with evidence of focal neuroendocrine differentiation using argyrophil (Bodian) and argentaffin methods. In 1981, Capella et al4 detected neuroendo-

tion; and (4) conventional adenocarcinomas, including undifferentiated carcinomas with evidence of ectopic/ eutopic hormone content by tissue analysis and/or hormone pro’duction as indicated by serum, plasma, or urine levels as well as tumors with associated paraneoplastic syndromes frequently related to neuroendocrine ditierentiation. Thirty-six cases were pure neuroendocrine malignancies, including 20 small cell/undifferentiated carcinomas, eight carcinoid tumors, and eight carcinoid-like tumors. Twenty-four cases were composite tumors, 10 were mixe’d adenocarcinoma and carcinoid (adenocarcinoid), and 14 were mixed adenocarcinoma and small cell/undifferentiated. Seventeen cases showed sequential progression over time from conventional adenocarcinema to neuroendocrine carcinoma, with the most common pattern of recurrence being small cell/undifferentiated carcinoma in 15 cases. One hundred fiftyeight case:3 were conventional adenocarcinomas with focal neuroendocrine differentiation. Conventional adenocarcinomas with eutopic/ectopic hormone content and/or production or with paraneoplastic syndrome included 29 cases. The term “carcinoid-like” was used in different ways by different investigators, but most commonly referred to cases with evidence of prostate-specific antigen and/or prostatic acid phosphatase produc293

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crine differentiation in 13 of 40 (32.5%) prostatic carcinomas using an argyrophil stain (Gremilius). In 1987, di Sant’Agnese and de Mesy Jensen’ detected neuroendocrine differentiation in 25 of 53 (47%) cases using a sensitive argyrophil stain (Churukian-Schenk) in combination with immunocytochemistry for generic neuroendocrine markers, serotonin, and a variety of specific peptides. Finally, in 1987, Abrahamsson et al,8 using similar staining methodology, found at least a minimal focal neuroendocrine differentiation in all 40 cases (100%) of prostatic tissues that were taken into Bouin’s fixative. Both eutopic and ectopic hormone content/production have been associated with prostatic malignancy (Table 1). Immunocytochemically detected eutopic hormones include serotonin, thyroid-stimulating hormonelike, somatostatin, calcitonin, and bombesin-like, with the most commonly reported being serotonin (53 cases) and thyroid-stimulating hormone-like (35 cases). Ectopic hormones detected by immunocytochemistry include adrenocorticotrophic hormone, beta-endorphin, alphaand beta-human chorionic gonadotrophin, parahormone, leu-enkephalin, and glucagon. Plasma, serum, and/or urine analyses in patients with prostatic malignancies have revealed the presence of adrenocorticotrophic hormone, calcitonin, antidiuretic hormone, beta-human chorionic gonadotropin, serotonin (5-hydroxyindolacetic acid in urine), and corticotropin-releasing hormone. Paraneoplastic syndromes reported include Cushing’s syndrome, inappropriate secretion of antidiuretic hormone, and hypercalcemia. The clinical significance of neuroendocrine differentiation in prostatic carcinoma has been studied by a variety of investigators. Small cell/undifferentiated carcinomas are very aggressive tumors, as they are elsewhere. Carcinoid tumors also appear to be quite aggressive in contrast to their generally relatively low-grade behavior in other primary sites.41 The degree of focal neuroendocrine differentiation in conventional adenocarcinoma also tends to directly correlate with the grade and aggressiveness of the tumors. It is not clear whether the aggressive behavior is a reflection of the neuroendocrine differentiation or merely the high grade of the tumors. It is not uncommon to see a progression from typical adenocarcinoma of the prostate with minimal or no neuroendocrine differentiation to frankly neuroendocrine carcinoma or carcinoma with marked focal neuroendocrine differentiation as the neoplasm becomes refractory to hormonal therapy. This raises the possibility that sex steroid hormonal receptors, most notably androgen receptors, are differentially expressed, or absent, in cells with neuroendocrine differentiation versus those without neuroendocrine differentiation. If androgen receptors were absent in malignant cells with neuroendocrine differentiation, this might explain progressive neuroendocrine differentiation as the neoplasm escapes from hormonal suppression as well as the general resistance of neuroendocrine neoplasms to hormonal therapy. There is minimal direct experimental evidence to support this hypothesis.“’ In ongoing immunocytochemical studies we are currently attempting to assess whether androgen receptors are expressed in malignant cells with neuroendocrine differentiation and 294

how this relates to androgen expression in conventional carcinoma cells in prostatic malignancy. We are also evaluating the presence or absence of androgen receptor in normal endocrine-paracrine cells. Again, it must be emphasized that neuroendocrine diflerentiation may be merely a reflection of increasingly poor differentiation in the neoplasms after hormonal therapy and not directly related to differential receptor content. Another area of interest is the use of neuroendocrine secretory products as potential markers to follow and/or screen for prostatic carcinoma. Neuron-specific enolase,“” chromogranin,‘” calcitonin,4.5 and bombesinrelated peptides 46 have all been used as markers for malignancies in other organ systems. These markers may be especially useful as a sensitive method to screen for those neoplasms likely to resist hormonal therapy or for the early detection of escape from hormonal suppression. This is especially important since hormonally resistant or escaping tumors are likely to be poorly differentiated and are apt not only to show neuroendocrine differentiation but also to frequently produce little or no prostate-specific antigen and prostatic acid phosphatase. There are a variety of more basic implications related to neuroendocrine differentiation in prostatic carcinoma. Bombesin-like peptides are a frequent secretory product of small cell carcinoma of the lung, with the same neoplastic cells expressing bombesin receptor. It has been further demonstrated that bombesin acts as an autocrine growth factor in small cell carcinoma of the lung. The same situation may pertain in prostatic malignancy with neuroendocrine differentiation as bombesin-like peptide production has been demonstrated in some of these neoplasms”,“7 and the presence of bombesin receptor has been shown to be expressed on an in vitro prostatic carcinoma cell line.” Bombesinlike peptides may also play a role in the earlier stages of carcinogenesis as has been experimentally demonstrated in the rat pancreas. Serotonin and catecholamines in general appear to have trophic/growth factor activity and have been shown to regulate normal growth and differentiation in the intestine.‘” Serotonin may also play an autocrine/paracrine growth factor role in prostatic carcinoma similar to that postulated for intestinal carcinogenesis and intestinal carcinoma.‘” It has been demonstrated in the guinea pig that there is a marked age-related increase of prostatic endocrine-paracrine cells and serotonin.‘” The relationship of this increased number of endocrine-paracrine cells and serotonin to carcinogenesis, which is a highly agerelated occurrence in the prostate, bears further investigation. It would certainly be of interest to see whether this age-related increase also occurs in humans. Another intriguing observation is the marked decrease in endocrine-paracrine cells in mature nodules of nodular prostatic hyperplasia (unpublished observation). Markedly decreased calcitonin levels in the nodules versus the normal prostate quantitatively corroborate this finding.‘” It is of further interest that small developing nodules focally contain abundant endocrine-paracrine cells (unpublished observation). Whether endocrineparacrine cells are involved in the actual pathogenesis of nodular prostatic hyperplasia remains to be seen.

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(P. Anthony di Sant’Agnese)

12. Casanova S, Corrado F, Vignoli G: Endot rine-like cells in the epithelium of the human male urethra..\ SubmivI-osc Cycol 6:435438. 1974 13. Lendon RG, Dixon JS, Gosling JA. The distribution of rndocrine-like cells in the human male and female urethral epithelium. Experientia 32:377-378, 1976 14. di Sant’Agnese PA, de Mesy Jensen KL: Endocrine-paracrine (APUD) cells of the human female urethra and paraurrthral ducts. J Llrol 137:1250-1254, I987 15. Fetissof F. Dubois MP. Larlson Y. et al: Endocrine cells in renal pelvis and ureter, an immunohistoc hrmical analysis. J Ural 135: 420421. I!)86 16. Fetissof F. Berger G. Dubois MP, et al: Endocrine cells in the female genital tract. Histopathology 9: I:I:1- 145, 1985 17. di Sant’Agnese PA: Endocrine aspects of the prostate, in Ixrhago J, Gould V teds): Bloodworth’s Endocrine Pathology (ed 3). New York, NY, Williams & Wilkins, 1992 (in press) 18. di Sant’Agnese PA, de Mesy.Jensen ICI.: Calcitonin, katacalcin and c-alcitonin gene-related peptide in the human prostate: An imn~unocytc~chenlical and immunoelectron microscopic study Arch Pathol I.ab Med 1 13:790, 1989 19. Davis NS: Determination 01 serotonin and 5-hydroxyindoleacetic acid in guinea pig and human prostate usinK HPLC. PI-ostatr 1 1:353-360. 1987 20. di Sant’Agnese PA: Calcitoninlike immunoreactive and bonlbesinlike immunoreactive endocrine-paracrinr cell\ of the human prostate. Arch Pathol Lab Med I IO:4 12-4 15, 1986 21. Fetissof F. Bertrand G, Guilloteau 1). et al: (Zalcltonin immunoreactive cells in prostate gland and cloaca1 de!-ived tissues. Vir-chows Arch [A] 409:523-533. 1986 22. di Sant’.kgnese PA, de Me% Jensen KL: Somatostatin and/ or somatostatinlike immunoreactive endocrine-paracrine cells in the human prostate gland. Arch Pathol I.ab Med 1OX:ti!t.?-696. I984 23. Fetissof F. Arbeille B, Guilloteau D, et al: (;lycopl-otein hormonr a-chairs-immurlo~-eactive endocrinr t-ells in prostate and cloacaderived tissues. Arch Patho Lab Med 11 1:836-840. 1987 24. Abrahamsson P-A, Lilja H: Partial c harac-teriLation 0f.a thyx-o&stimulating hormone-like peptide in neuromdocrine cells of the hutrrdn prostate gland. Prostate 14:7 l-81, l!)H!) 2.5. Davis NS. di Sant’Agnese PA, Ewing JF, ct .,I: ‘l‘he neurocrlclocrine prostate: Chardc-teri/.ation and quantitation of calcitonin in the human gland. J Ilrol 142:884-888. I!$89 26. Tutton PJM, Barkla DH: Biogenlc aminru as regulators of the proliferative activity of rrortnal alltl neoplastic intestinal epithrlial c ells (review). Anticancer Res 7: l-l 2. 19X7 “7. Zachax, 1. Woll PJ$ Rozengurt E: A role fi)r neulopeptidrb in thr control of cell pn)lifrration. Dcv Biot 1?4:2!)5-308, I987 28. Sylora HO, Diamond HM. Kaufman M. et ‘11: Primarv carcinoid tumor of the urethra. J Ural II-I: 150-1.53. I!175 29. Colby TV: Cal-c inoid tumor of the hladclcl : .AGIW report. .Arch Pathol I.ab Med 1O-1:199-200. 1980 30. Mills SE, Wolfr,JT, Weiss MA, et al: Small cell u~idiflerentiated carcinomaof the urinary bladder: A light-micros1 epic, itnrrlur~c~c-ytochenlid. and ultrdstl-uctlirdl stud\ of 12 I‘;w’s. .4n1 1 Surg Pathol ll:606-617. 19x7 31. di Sant’Agnese P.4: Neurc,euclo~rille diflerenti;ltion and pt-ostatic rare-inoma: The COIICept ‘( omrh of age.’ ;\I c.11Pathol Lab Med 1 12: 1097-l 099, 1988 (editorial) 32. Arumi N, Shibuyd H. Ishikum M: Pr-iman ]~I-ostatic c-arcinoid tumor with into-ac ytoplasmic prostatic acid phosphatase nnd prostatespecific antigen. Am J SKI-g Pathol 8:545-X0. 1984 3Y. Ghali VS. (;arcia RI,: Prostatic ;~tl~no~arcilloIna with cart inoidal features producing ~tdrrrlo~r)rtic.otropic svndrome: Immunohistochernic al stud) and review of the Iiteraturc. (:.mccl. 54: 10431048. 1984 (;: Thr, histogenesis of 34. Schron US. Gipson ‘f. Mel&l~ohll small cell carcmoma of the prclhtate: At1 irrllrlllrlot~istrl( hemical stud\. Cancer 53:247%248(J. I!184 35. Bleic hnrr,J(:. (:hun B. Klappenhach US: l’ur(, small-cell C~I r,inoma of the prostate with fatal li\rr- metdstasis. :Zrc.h P.tthol l.ah Med 1 lO:IO41-1044, 19X8 36. (;l~alldul.-Mrlaylrunetl I., Satterheld S. Bloc I, Nl.: Small trll cxcinoma 01 the prostate gland with inappt opriate ,mtidiurrtic hormone set retion: Mr,rphotogic dl. inllrlllllollistc,~ll~~llic al alItI c.linic al expressions. J t.:t-01 135:1263-l 266. t 986

Finally, not all products of endocrine-paracrine cells are stimulaltory with trophic/growth factor activity. Somatostatin, a product of normal prostatic endocrineparacrine cells” and secreted in some prostatic carcinomas.’ inhibits the secretory activity of a variety of endocrine-paracrine cell types in several different organ systems. Some of the secretory products inhibited by somatostatin have trophic/growth factor activity5”; therefore, somatostatin and its analogs have been used to treat some neuroendocrine neoplasms that may be hormonally driven. Somatostatin receptors have been demonstrated on prostatic endocrine-paracrine cells”‘.“2 and somatostatin has been shown to inhibit cellular cyclic adenosine monophosphate accumulation. Somatostatin analogs have been used to treat prostatic carcinoma with some beneficial results. The mechanism of response was initially thought to be entirely via the inhibition of prolac.tin secr’etion from the pituitary but evidence now suggests that a direct effect on the tumor may also occur.5” There are many potential implications of neuroendocrine diferentiation in prostatic malignancies. Some of these implications have been discussed in this review. It would be of great interest to determine whether neuroendocrine differentiation is a poor prognostic indicator independent of grade and whether androgen receptors are expressed in cells with neuroendocrine differentiation. Further work is needed to evaluate neuroendocrine peptide products associated with prostatic malignancy that might be used as new markers to follow prostatic carcinoma. The potential expression of receptors for- these products on neoplastic cells also needs to be evaluated and may lead to more effective treatments for prostatic carcinoma. REFERENCES I, l’rrtl K: %LII Irage tlrr rndokrinie der mensc-hlic hrn vorstehyrtlrusr. Vii-chows AI-Ch [A] 3 I t’:SW-404. 1944 2. Fryrt~:l- F: Ubrr das urogenitale helle-/elIen-

Neuroendocrine differentiation in human prostatic carcinoma.

Endocrine-paracrine (APUD, neuroendocrine) cells are located in the prostatic ductal and acinar epithelium. These cells are of the open and closed typ...
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