- Email: [email protected]
Prostate cancer—Quo vadis?
Prostate Cancer-Quo
Vadis?
C. S. FOSTER,
AND
MD,
PHD,
MRCPATH,
This symposium has addressed the current status of our collective understanding of the pathobiology of human prostate cancer. During recent years, a large amount of data have been generated from which general behavioral trends by groups of tumors within prostate cancer may be predicted. However, not all primary prostatic carcinomas exhibit a similar lethal potential. Furthermore, conventional therapy appears to be of little value in controlling phenotypically malignant primary tumors, whether confined to the prostate gland or spread to tissues beyond the confines of the capsule. Hence, a major dilemma in the management of prostate cancer is that clinically unimportant cancers do not require aggressive treatment (from which patients should be spared to lessen overall morbidity) while clinically important cancers cannot be specifically identified while they are still curable. Therefore, the principal objective of this symposium was to examine the wealth of information that has recently become available about prostate cancer to determine whether there are now any reliable indicators of human prostate cancers. This symposium has emphasized the need for further research and has outlined some of the directions in which new investigations are most likely to be fruitful. EARLY
PROSTATE
CANCER
Scardino, Weaver, and Hudson have defined the sharply rising incidence of human prostate cancer. Their quoted figures have clearly indicated the accelerating social and economic implications of this disease if it is not treated more successfully than at the present time. Although the epidemiology of human prostate cancer remains unknown, it is clear that identification and early treatment, particularly while it is still within the confines of the prostatic capsule, is the only certain method of reducing the associated mortality, and possibly morbidity, of this disease. However, the problem remains of differentiating those small prostatic cancers requiring urgent treatment from morphologically similar lesions that behave in a relatively indolent manner. Disparities between morphologic appearances and functional biologic phenotypes of individual prostate cancers have From the Royal Postgraduate Medical School. Hammersmith Hospital. London, UK; and the Armed Forces Institute of Pathology. Washington. DC. Dr Foster acknowledges the Stanley Thomas Johnson Foundation and the Albert McMastcr Fund of the British Medical Association for contributing funds that support aspects of human proswe cancer research in the Department of Histopathology at the Royal Postgraduate Medical School, London, UK. Address correspondence and reprint requests to C. S. Foster. MD, PhD, MRCPath, Department of Histooatholow. Royal Postgraduate Medical School, fiammersmith Hos$tal, D;‘i:ane kd. I.ondon, W12 ONN, UK. Copyright 0 1992 by W.B. Saunders Compaq 004~-x177/9?/?304-0008$5.00/0
402
F.
K.
MOSTOFI,
MD
emphasized a realization that comprehension of the fundamental biolog)i of this disease is lacking in many areas. The proposal to perform a large-scale, fully randomized clinical trial to compare the cancer-specific mortality rates in screened and unscreened populations is laudable. Unfortunately, the magnitude of the task and the length of time required to complete it will, almost certainly, cause it to remain a cherished but unrealized ambition until appropriate molecular probes are available with which to screen the male population and identify those individuals at risk. Correct identification of the earliest (ie, premalignant) lesions is of paramount importance if the true pathobiology of prostate cancer is to be understood. This situation has become more complicated by the introduction of various terms by different investigators, as discussed by Mostofi and Brawer in this symposium. The introduction of hiopty in the clinical investigations of prostatic carcinoma has magnified the pathologist’s problem in diagnosing prostatic carcinoma. Mostofi et al have endeavored to clarify the criteria for pathologic diagnosis of prostatic carcinoma for those lesions that simulate prostatic carcinoma and for their differential diagnosis. “Prostatic intraepithelial neoplasia” (PIN) is a term that has been recommended for one category of premalignant lesions to replace the term “dysplasia.” It is hoped that Brawer and Mostofi have clarified the situation. Two distinct categories of premalignant lesions are now recognized: PIN, which is characterized by intraacinar proliferation, and neoplasia of the secretory cells with no evidence of new gland formation. Considerable evidence has been presented that this latter category progresses to some, although not all, infiltrating prostatic carcinoma. Prostatic lntraepithelial
Neoplasia
Support for PIN as a precursor of some prostate cancers includes studies that have revealed twice the incidence of this lesion in prostates with cancer when compared with those without cancer.’ However, it is not the precursor of all prostatic cancers. When the criteria of Bostwick and Brawer were applied to radical prostatectomy specimens containing invasive cancer, all were found to contain foci of intraepithelial neoplasia, provided that sufficient material was examined.” Ideally, the presence of a continuous layer of basal cells surrounding the intra-acinar neoplastic cells facilitates and confirms the diagnosis of the lesion. In many instances, however, the basal cell layer is either discontinuous or absent, and one has to depend on intact basement membranes and the recognition of the earliest stages of invasion, as described by Mostofi. Since in patients younger than 60 years of age, PIN is frequently associated with prostatic carcinoma, it is imperative that all available pathologic material and additional sections be studied and that the urologist be alert to the fact that
HUMAN PROSTATE
~hr paticlll
ma\’ 11ave (.arcinoma elsewhere lesion indicxtr; high risk for de~x+q~menl (2rcinoma in tllis agr group.
CANCER-QUO
quently iu the peripheral, ho~~seshoe-sll;~1~ed rc@on in the posterolateral aspect to the prostate, 111~re@m now referred to as the peripheral zone. There is le5s agreement with the concept of a pure Iratlsitioll z01ie carcint )III;I of characteristic cytologic appea~.ance,~ which is suggested to comprise 24% of all prostatic rnalig7iancie~.” McNeal’s transition zone is difficult to recognize in oltl~r patients. The distinction between the ~~ltral. trxlsition. and peripheral Lanes. based 011 a positive reaction of’ the central zone to pepsinogen II, i cannot he confirmed as the polyclonal rabbit antiserum is not generatlv available. Mch’ral’s data suggest that peripheral zc& C~JIr’ers, whether or not they ha\:e penetrated the capsule, cx~mmonly do not enter the transition zont’. Helice, thq are either not detected or they are urlder\alued in their probable volume. According to McNeal, detailed esamillarion of small prostatic. tumors found incidentally and (4 large ~mcers presenting with symptoms has indicated ;I strong COJ‘relation between Gleason grade and tumor volunie.s .4 filrther correlation has been demons~ rated between prevalence tjflargc prostatic neoplasms fi~urid at autopsy and clinical incidence and mortality rate of’disseminated prostatic. cancer. According to McNeal, approximateI) 20Y0 of “latent” cancers found incidentally at autops! are sufficiently large to be potentially lifis threatening. That high incidence of large, latent prosl.atic cancers is, in fact, related to the high incidence of clinic al carcinomas ,ind to death from prostatic cancer, a5 was rcported by Breslow et al” in a study sponsored by thr International Agency for Research in (:ancer. These investigators reported that the incidence of small cancers was the same in seven different locations (Hong Kong. Singapore, Israel, Uganda, (Germany. Sliceden, and .]amaica), hut the incidence of’ large tumors varied geographicallv. ‘I‘he incidence of large tmllors was lowest intermediate in Israel in Hong Kong and Singapore, and LJganda, and highest in (;ermanv. Sweden. and Jamaica. These rates correspond to c,linil: aI de;lth rates f’rom prostatic cancer in these loc.ation~. McNeal has emphasized Franks’ original concept of “latency.” in which it was suggested that there appeared to he two phenotypically distinct species of prostati(, adcanocarcinoma.” He has concluded that the uniquely broad range of histologic differentiation seen in prostate cancer is a morphologic reflection of biologic progression. LJnfortunatelv. these are comparative data obtained from different individuals with morphologicall)similar tumors, for which furlctional and behavioral c.haracteristics arc unknown.
or that the of prostatic
New Giand Formation 111rl~f:, src~or~tl category of prrmalignant lesions thrrc is new gland formation, as evidenced 1))’ prolif~l~atioli 01 small a&i. In this group there is abnormal distrihutioIi of rhe newly formed acini, hut with equivoc,al or ahsmr nuclear atypia. This category is variously dt5ignated as “atypical adenomatous hyperplasia” 01 “;itypicA ghtls,” and these lesions may he precursors of low-grade. will-differ-entiated prostatic c‘arc~iriomas. b’ith ilicrcasing frequency. differentiation of henign from ~\-ell-difttrentiated ac~enoc~lr~inonla rests with strict c\,tologic. criteria. In this symposium. Eble and .4nge&eirr have examined needle core biopsy and fine nc~llc cvtcAogic, sampling in the diagnosis of early prosr;itr cancw. I II Europe, particularly ill Scandinavian c~uri~ri~s, tinr needle cvtologic. sampling is routinel) used. Howcw~. in thr Lrnitcd States technical difficulties iti collection of’suc-h specimens arid the need for special trairling to interpret c~ytologic smears have limited the use of c~~tolog~ in thr diagnosis of prostatic carcinoma. ‘l‘ht* avaklhilitv of tissue from fine needle hiopty has rc~placed 1he use of‘ cvtology. In cytolog); and biopty. tile absolute necessity of studying nuclear anaplasia has beet1 emphasized. The studies of Bonney et aI” showed tliat between four and eight cores of prostatic tissue \ver-e required to routinely achieve a satisfactory level of sensitivity in detecting clinically unapparent cancers. Of the difercnt studies examined, false positives may be considered to he nil, whereas false negatives OCCUI at ;I rate of’ approximately 10% in needle core biopsies. b’l1e11 inadequate samples ancl technical artifacts were excluded. bne needle aspiration cytology yielded sinlila] figures. M.ilh ;I f,ilse-positive rate of less than 1%. ESTABLISHED
PROSTATE
VADIS? (Foster & Mostofi)
CANCER
111his. WI iew. McNeal extended his earlier concepts 011 the or++ ant1 development of prostatic carcinoma to show a correlation between prostatic cancer volume, histologic g~xte, and metastasis. Accurate data obtained f1~11 studies of the type performed in the LJnited States and Canada, as detailed by Mostofi et al, are of paramount importance to a better understanding of prostate cancer prc )qession. Unfortunately, in Great Britain and other European countries where radical prostatectomy for carcinoma is performed only infrequently, detailed examination of anatomically intact prostatectomy specimens in numl,ers sufficient to provide reliable biologic or patholc)gic data is not presently feasible. Such processing of the total prostatectomy specimen, properly sectioned at 2.5mm intervals and then mapped, has provided accurate analysis of the sites of prostatic cancer and its rel,ationship to PIN and adenomatous hyperplasia, and has correlated pathology with imaging findings. McNeal’s concept of the anatomy of the prostate gland is illteresting. It has long been known that most prostatic <.arcinomas originate and are found most fre-
GRADING
PROSTATE
CANCERS
Three factors underlie recent effi>~ 1s to quantify structural features of prostate cancer. First is the concept of tumor progression defined by Foulds, who stated that saucers do not express their full range of malignant biologic attributes from the outset, hut rather progress toward increasing malignancy with time.’ ’ Support fog this thesis has come from the second fac.(ot-. ret-ognition of tumor cell heterogeneity. and from :I spontaneous 403
HUMAN PATHOLOGY
Volume 23, No. 4 (April 1992)
emergence of new biologic phenoty es, such as metastatic ability and drug resistance.‘?.‘. Y However, Foulds appeared not to appreciate the third factor, that of the relationship between tumor morphology, tumor biology, and time. McNeal subsequently proposed that biologic progression of prostate cancer directly correlates with tumor volume and hence has identified this parameter to be central to predicting biologic behavior.‘” The importance of tumor volume has been long recognized in clinical stage classification of all tumors. Broders15 first formulated the concept of comparing the architectural morphology of a tumor with the usual appearance of its nonneoplastic tissue of origin. The concept underlying grading was that, within any tumor, specific features are present that relate to the functional biology of that particular disease. Such features may be morphologic or they may be the expression (or nonexpression) of specific cell-associated molecules and may be detected using various criteria. In the prostate, over 30 different grading systems have been published. In 1978, in an effort to standardize grading of prostatic carcinomas, the National Prostate Cancer Project recommended that, for the purpose of analysis of clinical experience, the Gleason system be tentatively used and that nuclear and cytologic characteristics be considered in prospective studies.‘” Gleason has described in detail his grading system, and that is the system currently being used in many laboratories both in the United State and in the United Kingdom. In his review, Mostofi has briefly described three other systems based on nuclear anaplasia and/or differentiation. A grading system based on three grades of nuclear anaplasia and four grades of histologic differentiation was initially proposed by the World Health Organization (WHO) in 1977.” Used individually or combined together, the WHO system has been found to provide a good prognostic index, comparable to that of Gleason. Gaeta” based his grading system on the worse of the two, while the M. D. Anderson c1assification1g grades on the basis of differentiation. All grading systems recognize good tumors and bad tumors. The problems with all grading systems are reproducibility and the facts that most tumors fall in the intermediate group and that none of the groups is applicable to any individual patient. The Gleason system is not applicable to biopties, in which only a few glands or cells are available for pathologic diagnosis. It may be mentioned that both the International Union Against Cancer and the American Joint Committee for Clinical Stage Classification require that the WHO classification be used in all reports. The reported frequency of “incidental” microcarcinemas in association with overt infiltrating “macrocarcinomas” is an important observation and further supports the notion of a multifocal origin of prostatic carcinoma. A significant aspect of earlier work was the suggested association between “dysplasia” and microcarcinomas. The generally held inference that “. . .invasive carcinomas usually develop from dysplasia.. .” caused considerable confusion.” Examination of the papers by McNeal, Brawn, and Gleason highlights a point of fundamental disagreement in understanding 404
the basic biology of human prostate cancer. It is not yet known with certainty whether naturally occurring prostate cancers begin as well-differentiated tumors and “dediflerentiate” or, as Gleason suggests, whether these neoplasms have relatively fixed degrees of biologic malignancy and grow at relatively fixed rates with only infrequent and mild changes to higher malignancy. An alternative is that in cancers that progress, there are more malignant elements not recognized by hematoxylin-eosin that become predominant. Nevertheless, welldifferentiated tumors are also capable of invasion and metastasis. McNeal’s implied assumption that metastatic spread of prostate cancer occurs infrequently before capsular penetration is challenged by the finding of well-differentiated carcinomas in lymph nodes. According to McNeal, such differentiation should occur only in very small carcinomas, which would neither have breached the prostatic capsule nor have metastasized. Brawn’s explanation is that the initial metastases are usually moderately differentiated because “they occur after the morphology of the primary tumor has progressed through moderate to poor differentiation.” Options for the mode of metastatic spread of prostate cancer range from a rigorous progression favored by McNeal (supported by his data on tumor grade and volume) to the random hypothesis of Paget in which metastatic disease could occur at any time.” Histologic examination of metastases is presently the most accurate method of predicting prognosis of Whitmore stage D, prostate carcinomas. Distinct differences in length of diseasefree survival have been identified between node-negative patients and those with minima1 pelvic node metastases. In this latter group, those with moderately differentiated metastases exhibited significantly better rates of survival than did those with poorly differentiated metastases. Unfortunately, these data reflect the recurring problem of being able to demonstrate features of apparent value in predicting the future behavior of groups of prostate cancers while being of insufficient practical value to predict the behavior of individual patients. With respect to the value of morphologic appearances of metastases within a lymph node when the primary carcinoma is occult, Brawn clearly emphasized that whenever such metastases are composed entirely of single malignant glands they are unlikely to be derived from a prostatic primary carcinoma. Unless a metastatic tumor resembles prostatic carcinoma, it should not be so diagnosed. In their section of this symposium, Allsbrook and Simms and di Sant’Agnese have each emphasized the need for detailed studies of cell types, not only by examination of routine hematoxylin-eosin sections, but also by application of immunopathology. di Sant’Agnese has called attention to neuroendocrine cells in prostatic carcinoma and the existence of carcinoids and small oat cell-like tumors of the prostate. These are entities that have received little attention in the past from pathologists. The influence of neuroendocrine cells in response to therapy and the effect of survival and mortality rates of patients with prostatic carcinoma have opened a vast new role for pathology in the management of patients with prostate cancer.
HUMAN PROSTATE
CANCER-QUO
VADIS?
QUO VADIS? ‘llw abilit! tc) identify cancers that will behave in a mamler is one of the most sought-after goals cbf presenr-day path&by. This is yet to be achieved in any of the mafor solid malignancies, including prostate cancer. Review of the present status of prostate cancer biology,. a~ described in this symposium, has emphasized two pomt:;. First, the need for detailed study of the malignant prostatic epithefiaf cell since the behavior of any tumor depends on the structural composition of the incfivitfuaf c.ells. Research aimed at identifying individual phenotypes within a tunlor population is urgently required. The second point is the need for standardization. Failure to standardize the various approaches. definitions, and. criteria by different investigators is a major factor in the current impaired understanding of &is disease. This being so, it is hardly surprising that clinicians have been unable to treat, in a differential and biofogicalf~~ appropriate manner, patients identified to have apparently cliflerent phenotypes of prostate cancer. As an initial and practical step toward obtaining nlore compal-able data, and hence developing a greater understanding of the pathobiology of human prostate cancer. we now suggest the f’ollowing guidelines. These havr heen divided into three sections. The first section comprises those investigations considered to be fundamental to obtaining the minimum data necessary to report the surgical pathologic findings of prostatic carcinoma. The se&d comprises investigations that should be performed routinely if facilities and time are avaifable. The third outlines those avenues of research considered most fikelv to yield information that wilt lead to a better understanding of the pathobiofogy of prostatic cancer, it.5 management, and its possible control. In outlining these proposals, an obvious conflict between routine diagnostic requirements and research requirements becomes apparent, particularfv with respect to I he processing of intact prostatectomy specimens. We suggest that valuable information concerning the anatomic occurrence and distribution of‘ prostate c’ancers may he obtained routinely by laboratories adopting a conventional approach to handling theit specimens and reporting their observations. Biochemical and molecular analyses of unprocessed prostatectomy specimens should be performed in collaboration with research laboratories. Intact prostatectomy specimens should he sliced and examined macroscopically prior to fixation in order to select regions not essential for diagnostic f>urposes, which may then he preserved in a manner a.ppropriate for the intended research. particular
Section 1: Routine minimum anatomic pathologic invesfigotions
I
rransurethral resection chippings a. (:hippings should be weighed and foul cassettes should be embedded. Thereafter, one additional cassette should be filled for each 10 g of tissue. b. If microscopy reveals cancer, additional material should be processed to deter-
‘) _.
(Foster & Mostofi) mine, as accuratelv as f>osSibfr. the vofunlr of that cancer. Total prostatectomy specimena In those instances-in which facilities fi)r collaborative research are not available, specimens should be weighecf, measured, and suspended in tixative overnight. The surface should he marked with ink prior to slicing the specimen at ‘I..?mm intervals in the plane pcrpendicufar~ to the rectal surface, using a meat curter-. The slices sf~oulcf be laheled serially. If facilities art available. whole-molmt sections shoulcf he prepared and three-tfimensionaf reconstruction performed. This is the onI\ method by which pathologic tinclings can be coordinated with magnc.tic resonance imaging. Sections of’ the base and aflex should be cut at right anglrs to detect the presence of tumor in those regions. If fitcilities for whole section aw not available.
the blocks may he cut illto four pieces and orientated as to their t’xact location. I~feally, all the slices shouftf he processed. However, if facilities are limitecf. blocks must he made from alternate sfic-es. In such cases, if a cancer is identified following microscopy, additional lot al blocks should be take11 to quantifj. as accurateI)
Xi possible, the volume of that c;mcer. 3a. The criteria proposed hy, Brawer and Moscofi should he used to identlfv PIN and atypical adenomatous hyperplasia, which must be reported routinely. If there is a problem in recc )gnizing basal cells, antibodies to cytokei-alins 5 and 14 should be used to detect these cells imrrt~lnohistochellically. Presence of basal cells should be adopted
as the criterion of PIN. or World Health Organization grading system should he usecf and reported in every case. The Gleason svstem may not he applicable to biopties or to c! tology and, in such cases, grading shouftf he based on nuclear anaplasia. 5. Information relative to 1he tumor vofume should he provided in every case. For hiopties/biofxies, a statement relative to how much of the specimen comprises cancer is necessary. For incidental prostatic carcinomas, the number of pieces showing cancer, the percentage of cancer, and the de
1. The Gleason
Section 2 Supplementary
investigations
6. Fine needle aspiration cytologic examination may be used. However. at the present time, in the United States tissue exdminacion is the accepted mode of pathologic diagnosis of prostate cancer. 405
Volume 23, No. 4 (April 1992)
HUMAN PATHOLOGY
computer-based morpossible, 7. W’henever phometry should be performed to measure tumor volumes. If such facilities are not available, proportions of tissue occupied by cancer should be reported. every prostatic carcinoma 8. At diagnosis, should be investigated for neuroendocrine cells by immunohistochemical staining for neurone-specific enolase and chromogranin and their presence should be reported. When the prostatic origin of a tumor is in doubt, prostatic-specific antigen should be identified immunohistochemically. If this is negative, prostatic acid phosphatase could be assessed immunohistochemically, although a selective and reliable antibody to it has yet to be developed for routine use. However, some prostatic cancers are negative for both. 0. . When facilities are available DNA analysis by flow cytometry, either of fresh tissue or disaggregated formalin-fixed tissue, is desirable since it adds another dimension for prognostic capabilities. Nevertheless, the value of the obtained information is limited, even from expert laboratories where the data are reliable. 10. Karyotypic analysis of chromosomes is desirable. Se&ion
3 Speciolisf
investigafions
Patients belonging to “cancer families,” particularly those with fathers/brothers/sons with prostate cancer and those men with mothers/sisters/daughters with breast cancer, are likely to be at high risk and should be screened regularly from the age of 40 years. Screening should comprise serum prostate-specific antigen, digital rectal examination, and either transrectal ultrasonography or magnetic resonance imaging. DNA studies should include analysis of chromosomes 2, 7, 10, and 16 in particular and a search should be made fol regions of consistent loss or rearrangement. Although current information indicates there is no role for molecular probes or oncogenes in the assessment of prostate cancer histology, investigation of these tumors for gene rearrangements and/or deletions might reveal regions of the genome important in prostate cancer, possibly novel tumor suppressor genes. Other features of prostatic cancer cells should be sought, particularly expression of determinants relating to behavioral features, such as metastatic ability and drug resistance, as new immunologic and molecular probes become available. Close combined working collaboration should be encouraged between clinicians and basic scientists. The objective of such collaboration will be to use all available modalities to identify, biopsy, and, whenever necessary, treat prostate cancer at its earliest stages. Thereafter, the same combination of modalities should be directed toward identification of recurrent disease. In conclusion, the single most valuable step toward a better understanding and hence management of hu-
406
man prostate cancer will be the unified and standardized approach to obtaining, recording, and interpreting those data that are currently achievable. Future goals should concentrate on the identification and application of biochemical and molecular reagents that may be used on fresh or conventionally processed tissues to accurately define those molecular events resulting in diEerent functional/behavioral phenotypes and that comprise the biologic heterogeneity of human prostate cancer. Acklrowl~r~~mc,,~~. The helpful advice on reviewing
authors thank the manuscript
Dr
Paul
Abel
I’OI
REFERENCES 1. Bostwick
IK:
Prostatic
intraepithrlial
neoplasia.
Llrolo~~ 34:
16-2. 1089(suppl) 2. Bostwick DC;, Brawer- MK: Prostatic intra-epithelial neoplasia and early invasion in prostate canter. (:anccr .59:788-794, 1987 3. Bonney WW. Robinson RA. I.achenhruch PA, et al: Yield of. cancer tissue from prostatic needle biopsy. Urolo~ 29: 153- 156. I987 4. Agatstein EH, Hernandez FJ. I.ayfield LJ. et al: Clsr of fine needle aspiration for detection of stage A prostatic cal-cinema befol-e transurethral resection of the prostate: A clinical trial. J LTI-oI 13X: .5.51-.i.53, 1987 5. McNeal JE: Normal histology of the prostatr. .4m J Surg Pathol 12:6 1o-ti33, 1988 6. McNeal JE. Reclwine LA, Freiha FS, ct al: Zonal distribution of pl-ostatic adenocar~inorna: Correlation with histologic pattern and direction of spread. Am J Surg Pathol I2:897-906, 1988 7. Reese JH. MrNeal JE. Redwine EA. et al: Tissue type plasminogen activator as a marker fox- functional zones within the hutnan prostate gland. Prostate 12:47-53, 1988 8. McNeal JE: Morphologic indices of progrrssion in prostatic carcinoma, in Coffey IX, (Ltrdner WA, Bruchovsky N, et al (eds): Curr-ent Concepts and Approaches to the Study of Prostate (:ancrr. New York. NY, Liss. 1987. pp 779-782 9. Breslow M. Ghan CW. Whom G, et al: I,atent carcinoma of prostate at autopsy in seven areas. Int J Cancer 20:680-688. 1977 10. Franks LM: Latent carcinoma of prostate.,J Pathol Bactrriol 68:603-610. 195-l 1 1. Foulds I.: The exper-imental study of tumour progl-ession: A review. Cancer Res 15:327-339. 19.54 12. Paste G, Grieg R: On the genesis and regulation of cellular heterogeneity in malignant tumors. Invasion Metastasis 2: 137-l 76, I982 13. Fidler IJ. Hart R: Biologic diversity in metastatic nroplasms: Origins and implications. Science 217:998-1003. 1982 11. McNeal JE, Bostwirk IX, Kindrachuk RA, et al: Patterns of progression in prostate cancer. Lancet l:(iO-63, 1986 Ii. Broders AC: Carcinoma. Grading and practical application. Ar-ch Pathol 2:376-38 I, 1926 16. Murphy GP, Whitmore WF: A report of the workshops on the curl-em status of the histological grading of prostatic cancer. Cancel 44: 1490-l 494, 1979 17. Mostofi FK, Sesterhenn IA. Sohin IH: International Histological Classification of Prostate Tumors. Geneva. Switzerland. World Health Organization. 1980 18. Gaeta JF, Asirwatham JE, Miller G. et al: Histological grading of primary prostatic cancer: A new approach to an old problem. .J Ural 123:689-6x3, 1080 19. Brawn PN. Avala AA, Eschenbach AC, 1-t al: Histologjcal grading and study of l&static adenocarcinoma: Development of a new system and comparison with other methods. Cancrr -19: I 13-190. 1982 20. McNeal JE, Villiers A, Redwine EA. et al: Microcarcinoma of the prostate: Its association with duct-acinar dysplasia. HLIMPATHOI 22:644-652, 1001 2 1. Paget J: The distribution
the brrast.
I.ancet
1:571-573.
1889
of secondary
gl-owth in cancel
of
Vadis?
C. S. FOSTER,
AND
MD,
PHD,
MRCPATH,
This symposium has addressed the current status of our collective understanding of the pathobiology of human prostate cancer. During recent years, a large amount of data have been generated from which general behavioral trends by groups of tumors within prostate cancer may be predicted. However, not all primary prostatic carcinomas exhibit a similar lethal potential. Furthermore, conventional therapy appears to be of little value in controlling phenotypically malignant primary tumors, whether confined to the prostate gland or spread to tissues beyond the confines of the capsule. Hence, a major dilemma in the management of prostate cancer is that clinically unimportant cancers do not require aggressive treatment (from which patients should be spared to lessen overall morbidity) while clinically important cancers cannot be specifically identified while they are still curable. Therefore, the principal objective of this symposium was to examine the wealth of information that has recently become available about prostate cancer to determine whether there are now any reliable indicators of human prostate cancers. This symposium has emphasized the need for further research and has outlined some of the directions in which new investigations are most likely to be fruitful. EARLY
PROSTATE
CANCER
Scardino, Weaver, and Hudson have defined the sharply rising incidence of human prostate cancer. Their quoted figures have clearly indicated the accelerating social and economic implications of this disease if it is not treated more successfully than at the present time. Although the epidemiology of human prostate cancer remains unknown, it is clear that identification and early treatment, particularly while it is still within the confines of the prostatic capsule, is the only certain method of reducing the associated mortality, and possibly morbidity, of this disease. However, the problem remains of differentiating those small prostatic cancers requiring urgent treatment from morphologically similar lesions that behave in a relatively indolent manner. Disparities between morphologic appearances and functional biologic phenotypes of individual prostate cancers have From the Royal Postgraduate Medical School. Hammersmith Hospital. London, UK; and the Armed Forces Institute of Pathology. Washington. DC. Dr Foster acknowledges the Stanley Thomas Johnson Foundation and the Albert McMastcr Fund of the British Medical Association for contributing funds that support aspects of human proswe cancer research in the Department of Histopathology at the Royal Postgraduate Medical School, London, UK. Address correspondence and reprint requests to C. S. Foster. MD, PhD, MRCPath, Department of Histooatholow. Royal Postgraduate Medical School, fiammersmith Hos$tal, D;‘i:ane kd. I.ondon, W12 ONN, UK. Copyright 0 1992 by W.B. Saunders Compaq 004~-x177/9?/?304-0008$5.00/0
402
F.
K.
MOSTOFI,
MD
emphasized a realization that comprehension of the fundamental biolog)i of this disease is lacking in many areas. The proposal to perform a large-scale, fully randomized clinical trial to compare the cancer-specific mortality rates in screened and unscreened populations is laudable. Unfortunately, the magnitude of the task and the length of time required to complete it will, almost certainly, cause it to remain a cherished but unrealized ambition until appropriate molecular probes are available with which to screen the male population and identify those individuals at risk. Correct identification of the earliest (ie, premalignant) lesions is of paramount importance if the true pathobiology of prostate cancer is to be understood. This situation has become more complicated by the introduction of various terms by different investigators, as discussed by Mostofi and Brawer in this symposium. The introduction of hiopty in the clinical investigations of prostatic carcinoma has magnified the pathologist’s problem in diagnosing prostatic carcinoma. Mostofi et al have endeavored to clarify the criteria for pathologic diagnosis of prostatic carcinoma for those lesions that simulate prostatic carcinoma and for their differential diagnosis. “Prostatic intraepithelial neoplasia” (PIN) is a term that has been recommended for one category of premalignant lesions to replace the term “dysplasia.” It is hoped that Brawer and Mostofi have clarified the situation. Two distinct categories of premalignant lesions are now recognized: PIN, which is characterized by intraacinar proliferation, and neoplasia of the secretory cells with no evidence of new gland formation. Considerable evidence has been presented that this latter category progresses to some, although not all, infiltrating prostatic carcinoma. Prostatic lntraepithelial
Neoplasia
Support for PIN as a precursor of some prostate cancers includes studies that have revealed twice the incidence of this lesion in prostates with cancer when compared with those without cancer.’ However, it is not the precursor of all prostatic cancers. When the criteria of Bostwick and Brawer were applied to radical prostatectomy specimens containing invasive cancer, all were found to contain foci of intraepithelial neoplasia, provided that sufficient material was examined.” Ideally, the presence of a continuous layer of basal cells surrounding the intra-acinar neoplastic cells facilitates and confirms the diagnosis of the lesion. In many instances, however, the basal cell layer is either discontinuous or absent, and one has to depend on intact basement membranes and the recognition of the earliest stages of invasion, as described by Mostofi. Since in patients younger than 60 years of age, PIN is frequently associated with prostatic carcinoma, it is imperative that all available pathologic material and additional sections be studied and that the urologist be alert to the fact that
HUMAN PROSTATE
~hr paticlll
ma\’ 11ave (.arcinoma elsewhere lesion indicxtr; high risk for de~x+q~menl (2rcinoma in tllis agr group.
CANCER-QUO
quently iu the peripheral, ho~~seshoe-sll;~1~ed rc@on in the posterolateral aspect to the prostate, 111~re@m now referred to as the peripheral zone. There is le5s agreement with the concept of a pure Iratlsitioll z01ie carcint )III;I of characteristic cytologic appea~.ance,~ which is suggested to comprise 24% of all prostatic rnalig7iancie~.” McNeal’s transition zone is difficult to recognize in oltl~r patients. The distinction between the ~~ltral. trxlsition. and peripheral Lanes. based 011 a positive reaction of’ the central zone to pepsinogen II, i cannot he confirmed as the polyclonal rabbit antiserum is not generatlv available. Mch’ral’s data suggest that peripheral zc& C~JIr’ers, whether or not they ha\:e penetrated the capsule, cx~mmonly do not enter the transition zont’. Helice, thq are either not detected or they are urlder\alued in their probable volume. According to McNeal, detailed esamillarion of small prostatic. tumors found incidentally and (4 large ~mcers presenting with symptoms has indicated ;I strong COJ‘relation between Gleason grade and tumor volunie.s .4 filrther correlation has been demons~ rated between prevalence tjflargc prostatic neoplasms fi~urid at autopsy and clinical incidence and mortality rate of’disseminated prostatic. cancer. According to McNeal, approximateI) 20Y0 of “latent” cancers found incidentally at autops! are sufficiently large to be potentially lifis threatening. That high incidence of large, latent prosl.atic cancers is, in fact, related to the high incidence of clinic al carcinomas ,ind to death from prostatic cancer, a5 was rcported by Breslow et al” in a study sponsored by thr International Agency for Research in (:ancer. These investigators reported that the incidence of small cancers was the same in seven different locations (Hong Kong. Singapore, Israel, Uganda, (Germany. Sliceden, and .]amaica), hut the incidence of’ large tumors varied geographicallv. ‘I‘he incidence of large tmllors was lowest intermediate in Israel in Hong Kong and Singapore, and LJganda, and highest in (;ermanv. Sweden. and Jamaica. These rates correspond to c,linil: aI de;lth rates f’rom prostatic cancer in these loc.ation~. McNeal has emphasized Franks’ original concept of “latency.” in which it was suggested that there appeared to he two phenotypically distinct species of prostati(, adcanocarcinoma.” He has concluded that the uniquely broad range of histologic differentiation seen in prostate cancer is a morphologic reflection of biologic progression. LJnfortunatelv. these are comparative data obtained from different individuals with morphologicall)similar tumors, for which furlctional and behavioral c.haracteristics arc unknown.
or that the of prostatic
New Giand Formation 111rl~f:, src~or~tl category of prrmalignant lesions thrrc is new gland formation, as evidenced 1))’ prolif~l~atioli 01 small a&i. In this group there is abnormal distrihutioIi of rhe newly formed acini, hut with equivoc,al or ahsmr nuclear atypia. This category is variously dt5ignated as “atypical adenomatous hyperplasia” 01 “;itypicA ghtls,” and these lesions may he precursors of low-grade. will-differ-entiated prostatic c‘arc~iriomas. b’ith ilicrcasing frequency. differentiation of henign from ~\-ell-difttrentiated ac~enoc~lr~inonla rests with strict c\,tologic. criteria. In this symposium. Eble and .4nge&eirr have examined needle core biopsy and fine nc~llc cvtcAogic, sampling in the diagnosis of early prosr;itr cancw. I II Europe, particularly ill Scandinavian c~uri~ri~s, tinr needle cvtologic. sampling is routinel) used. Howcw~. in thr Lrnitcd States technical difficulties iti collection of’suc-h specimens arid the need for special trairling to interpret c~ytologic smears have limited the use of c~~tolog~ in thr diagnosis of prostatic carcinoma. ‘l‘ht* avaklhilitv of tissue from fine needle hiopty has rc~placed 1he use of‘ cvtology. In cytolog); and biopty. tile absolute necessity of studying nuclear anaplasia has beet1 emphasized. The studies of Bonney et aI” showed tliat between four and eight cores of prostatic tissue \ver-e required to routinely achieve a satisfactory level of sensitivity in detecting clinically unapparent cancers. Of the difercnt studies examined, false positives may be considered to he nil, whereas false negatives OCCUI at ;I rate of’ approximately 10% in needle core biopsies. b’l1e11 inadequate samples ancl technical artifacts were excluded. bne needle aspiration cytology yielded sinlila] figures. M.ilh ;I f,ilse-positive rate of less than 1%. ESTABLISHED
PROSTATE
VADIS? (Foster & Mostofi)
CANCER
111his. WI iew. McNeal extended his earlier concepts 011 the or++ ant1 development of prostatic carcinoma to show a correlation between prostatic cancer volume, histologic g~xte, and metastasis. Accurate data obtained f1~11 studies of the type performed in the LJnited States and Canada, as detailed by Mostofi et al, are of paramount importance to a better understanding of prostate cancer prc )qession. Unfortunately, in Great Britain and other European countries where radical prostatectomy for carcinoma is performed only infrequently, detailed examination of anatomically intact prostatectomy specimens in numl,ers sufficient to provide reliable biologic or patholc)gic data is not presently feasible. Such processing of the total prostatectomy specimen, properly sectioned at 2.5mm intervals and then mapped, has provided accurate analysis of the sites of prostatic cancer and its rel,ationship to PIN and adenomatous hyperplasia, and has correlated pathology with imaging findings. McNeal’s concept of the anatomy of the prostate gland is illteresting. It has long been known that most prostatic <.arcinomas originate and are found most fre-
GRADING
PROSTATE
CANCERS
Three factors underlie recent effi>~ 1s to quantify structural features of prostate cancer. First is the concept of tumor progression defined by Foulds, who stated that saucers do not express their full range of malignant biologic attributes from the outset, hut rather progress toward increasing malignancy with time.’ ’ Support fog this thesis has come from the second fac.(ot-. ret-ognition of tumor cell heterogeneity. and from :I spontaneous 403
HUMAN PATHOLOGY
Volume 23, No. 4 (April 1992)
emergence of new biologic phenoty es, such as metastatic ability and drug resistance.‘?.‘. Y However, Foulds appeared not to appreciate the third factor, that of the relationship between tumor morphology, tumor biology, and time. McNeal subsequently proposed that biologic progression of prostate cancer directly correlates with tumor volume and hence has identified this parameter to be central to predicting biologic behavior.‘” The importance of tumor volume has been long recognized in clinical stage classification of all tumors. Broders15 first formulated the concept of comparing the architectural morphology of a tumor with the usual appearance of its nonneoplastic tissue of origin. The concept underlying grading was that, within any tumor, specific features are present that relate to the functional biology of that particular disease. Such features may be morphologic or they may be the expression (or nonexpression) of specific cell-associated molecules and may be detected using various criteria. In the prostate, over 30 different grading systems have been published. In 1978, in an effort to standardize grading of prostatic carcinomas, the National Prostate Cancer Project recommended that, for the purpose of analysis of clinical experience, the Gleason system be tentatively used and that nuclear and cytologic characteristics be considered in prospective studies.‘” Gleason has described in detail his grading system, and that is the system currently being used in many laboratories both in the United State and in the United Kingdom. In his review, Mostofi has briefly described three other systems based on nuclear anaplasia and/or differentiation. A grading system based on three grades of nuclear anaplasia and four grades of histologic differentiation was initially proposed by the World Health Organization (WHO) in 1977.” Used individually or combined together, the WHO system has been found to provide a good prognostic index, comparable to that of Gleason. Gaeta” based his grading system on the worse of the two, while the M. D. Anderson c1assification1g grades on the basis of differentiation. All grading systems recognize good tumors and bad tumors. The problems with all grading systems are reproducibility and the facts that most tumors fall in the intermediate group and that none of the groups is applicable to any individual patient. The Gleason system is not applicable to biopties, in which only a few glands or cells are available for pathologic diagnosis. It may be mentioned that both the International Union Against Cancer and the American Joint Committee for Clinical Stage Classification require that the WHO classification be used in all reports. The reported frequency of “incidental” microcarcinemas in association with overt infiltrating “macrocarcinomas” is an important observation and further supports the notion of a multifocal origin of prostatic carcinoma. A significant aspect of earlier work was the suggested association between “dysplasia” and microcarcinomas. The generally held inference that “. . .invasive carcinomas usually develop from dysplasia.. .” caused considerable confusion.” Examination of the papers by McNeal, Brawn, and Gleason highlights a point of fundamental disagreement in understanding 404
the basic biology of human prostate cancer. It is not yet known with certainty whether naturally occurring prostate cancers begin as well-differentiated tumors and “dediflerentiate” or, as Gleason suggests, whether these neoplasms have relatively fixed degrees of biologic malignancy and grow at relatively fixed rates with only infrequent and mild changes to higher malignancy. An alternative is that in cancers that progress, there are more malignant elements not recognized by hematoxylin-eosin that become predominant. Nevertheless, welldifferentiated tumors are also capable of invasion and metastasis. McNeal’s implied assumption that metastatic spread of prostate cancer occurs infrequently before capsular penetration is challenged by the finding of well-differentiated carcinomas in lymph nodes. According to McNeal, such differentiation should occur only in very small carcinomas, which would neither have breached the prostatic capsule nor have metastasized. Brawn’s explanation is that the initial metastases are usually moderately differentiated because “they occur after the morphology of the primary tumor has progressed through moderate to poor differentiation.” Options for the mode of metastatic spread of prostate cancer range from a rigorous progression favored by McNeal (supported by his data on tumor grade and volume) to the random hypothesis of Paget in which metastatic disease could occur at any time.” Histologic examination of metastases is presently the most accurate method of predicting prognosis of Whitmore stage D, prostate carcinomas. Distinct differences in length of diseasefree survival have been identified between node-negative patients and those with minima1 pelvic node metastases. In this latter group, those with moderately differentiated metastases exhibited significantly better rates of survival than did those with poorly differentiated metastases. Unfortunately, these data reflect the recurring problem of being able to demonstrate features of apparent value in predicting the future behavior of groups of prostate cancers while being of insufficient practical value to predict the behavior of individual patients. With respect to the value of morphologic appearances of metastases within a lymph node when the primary carcinoma is occult, Brawn clearly emphasized that whenever such metastases are composed entirely of single malignant glands they are unlikely to be derived from a prostatic primary carcinoma. Unless a metastatic tumor resembles prostatic carcinoma, it should not be so diagnosed. In their section of this symposium, Allsbrook and Simms and di Sant’Agnese have each emphasized the need for detailed studies of cell types, not only by examination of routine hematoxylin-eosin sections, but also by application of immunopathology. di Sant’Agnese has called attention to neuroendocrine cells in prostatic carcinoma and the existence of carcinoids and small oat cell-like tumors of the prostate. These are entities that have received little attention in the past from pathologists. The influence of neuroendocrine cells in response to therapy and the effect of survival and mortality rates of patients with prostatic carcinoma have opened a vast new role for pathology in the management of patients with prostate cancer.
HUMAN PROSTATE
CANCER-QUO
VADIS?
QUO VADIS? ‘llw abilit! tc) identify cancers that will behave in a mamler is one of the most sought-after goals cbf presenr-day path&by. This is yet to be achieved in any of the mafor solid malignancies, including prostate cancer. Review of the present status of prostate cancer biology,. a~ described in this symposium, has emphasized two pomt:;. First, the need for detailed study of the malignant prostatic epithefiaf cell since the behavior of any tumor depends on the structural composition of the incfivitfuaf c.ells. Research aimed at identifying individual phenotypes within a tunlor population is urgently required. The second point is the need for standardization. Failure to standardize the various approaches. definitions, and. criteria by different investigators is a major factor in the current impaired understanding of &is disease. This being so, it is hardly surprising that clinicians have been unable to treat, in a differential and biofogicalf~~ appropriate manner, patients identified to have apparently cliflerent phenotypes of prostate cancer. As an initial and practical step toward obtaining nlore compal-able data, and hence developing a greater understanding of the pathobiology of human prostate cancer. we now suggest the f’ollowing guidelines. These havr heen divided into three sections. The first section comprises those investigations considered to be fundamental to obtaining the minimum data necessary to report the surgical pathologic findings of prostatic carcinoma. The se&d comprises investigations that should be performed routinely if facilities and time are avaifable. The third outlines those avenues of research considered most fikelv to yield information that wilt lead to a better understanding of the pathobiofogy of prostatic cancer, it.5 management, and its possible control. In outlining these proposals, an obvious conflict between routine diagnostic requirements and research requirements becomes apparent, particularfv with respect to I he processing of intact prostatectomy specimens. We suggest that valuable information concerning the anatomic occurrence and distribution of‘ prostate c’ancers may he obtained routinely by laboratories adopting a conventional approach to handling theit specimens and reporting their observations. Biochemical and molecular analyses of unprocessed prostatectomy specimens should be performed in collaboration with research laboratories. Intact prostatectomy specimens should he sliced and examined macroscopically prior to fixation in order to select regions not essential for diagnostic f>urposes, which may then he preserved in a manner a.ppropriate for the intended research. particular
Section 1: Routine minimum anatomic pathologic invesfigotions
I
rransurethral resection chippings a. (:hippings should be weighed and foul cassettes should be embedded. Thereafter, one additional cassette should be filled for each 10 g of tissue. b. If microscopy reveals cancer, additional material should be processed to deter-
‘) _.
(Foster & Mostofi) mine, as accuratelv as f>osSibfr. the vofunlr of that cancer. Total prostatectomy specimena In those instances-in which facilities fi)r collaborative research are not available, specimens should be weighecf, measured, and suspended in tixative overnight. The surface should he marked with ink prior to slicing the specimen at ‘I..?mm intervals in the plane pcrpendicufar~ to the rectal surface, using a meat curter-. The slices sf~oulcf be laheled serially. If facilities art available. whole-molmt sections shoulcf he prepared and three-tfimensionaf reconstruction performed. This is the onI\ method by which pathologic tinclings can be coordinated with magnc.tic resonance imaging. Sections of’ the base and aflex should be cut at right anglrs to detect the presence of tumor in those regions. If fitcilities for whole section aw not available.
the blocks may he cut illto four pieces and orientated as to their t’xact location. I~feally, all the slices shouftf he processed. However, if facilities are limitecf. blocks must he made from alternate sfic-es. In such cases, if a cancer is identified following microscopy, additional lot al blocks should be take11 to quantifj. as accurateI)
Xi possible, the volume of that c;mcer. 3a. The criteria proposed hy, Brawer and Moscofi should he used to identlfv PIN and atypical adenomatous hyperplasia, which must be reported routinely. If there is a problem in recc )gnizing basal cells, antibodies to cytokei-alins 5 and 14 should be used to detect these cells imrrt~lnohistochellically. Presence of basal cells should be adopted
as the criterion of PIN. or World Health Organization grading system should he usecf and reported in every case. The Gleason svstem may not he applicable to biopties or to c! tology and, in such cases, grading shouftf he based on nuclear anaplasia. 5. Information relative to 1he tumor vofume should he provided in every case. For hiopties/biofxies, a statement relative to how much of the specimen comprises cancer is necessary. For incidental prostatic carcinomas, the number of pieces showing cancer, the percentage of cancer, and the de
1. The Gleason
Section 2 Supplementary
investigations
6. Fine needle aspiration cytologic examination may be used. However. at the present time, in the United States tissue exdminacion is the accepted mode of pathologic diagnosis of prostate cancer. 405
Volume 23, No. 4 (April 1992)
HUMAN PATHOLOGY
computer-based morpossible, 7. W’henever phometry should be performed to measure tumor volumes. If such facilities are not available, proportions of tissue occupied by cancer should be reported. every prostatic carcinoma 8. At diagnosis, should be investigated for neuroendocrine cells by immunohistochemical staining for neurone-specific enolase and chromogranin and their presence should be reported. When the prostatic origin of a tumor is in doubt, prostatic-specific antigen should be identified immunohistochemically. If this is negative, prostatic acid phosphatase could be assessed immunohistochemically, although a selective and reliable antibody to it has yet to be developed for routine use. However, some prostatic cancers are negative for both. 0. . When facilities are available DNA analysis by flow cytometry, either of fresh tissue or disaggregated formalin-fixed tissue, is desirable since it adds another dimension for prognostic capabilities. Nevertheless, the value of the obtained information is limited, even from expert laboratories where the data are reliable. 10. Karyotypic analysis of chromosomes is desirable. Se&ion
3 Speciolisf
investigafions
Patients belonging to “cancer families,” particularly those with fathers/brothers/sons with prostate cancer and those men with mothers/sisters/daughters with breast cancer, are likely to be at high risk and should be screened regularly from the age of 40 years. Screening should comprise serum prostate-specific antigen, digital rectal examination, and either transrectal ultrasonography or magnetic resonance imaging. DNA studies should include analysis of chromosomes 2, 7, 10, and 16 in particular and a search should be made fol regions of consistent loss or rearrangement. Although current information indicates there is no role for molecular probes or oncogenes in the assessment of prostate cancer histology, investigation of these tumors for gene rearrangements and/or deletions might reveal regions of the genome important in prostate cancer, possibly novel tumor suppressor genes. Other features of prostatic cancer cells should be sought, particularly expression of determinants relating to behavioral features, such as metastatic ability and drug resistance, as new immunologic and molecular probes become available. Close combined working collaboration should be encouraged between clinicians and basic scientists. The objective of such collaboration will be to use all available modalities to identify, biopsy, and, whenever necessary, treat prostate cancer at its earliest stages. Thereafter, the same combination of modalities should be directed toward identification of recurrent disease. In conclusion, the single most valuable step toward a better understanding and hence management of hu-
406
man prostate cancer will be the unified and standardized approach to obtaining, recording, and interpreting those data that are currently achievable. Future goals should concentrate on the identification and application of biochemical and molecular reagents that may be used on fresh or conventionally processed tissues to accurately define those molecular events resulting in diEerent functional/behavioral phenotypes and that comprise the biologic heterogeneity of human prostate cancer. Acklrowl~r~~mc,,~~. The helpful advice on reviewing
authors thank the manuscript
Dr
Paul
Abel
I’OI
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IK:
Prostatic
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16-2. 1089(suppl) 2. Bostwick DC;, Brawer- MK: Prostatic intra-epithelial neoplasia and early invasion in prostate canter. (:anccr .59:788-794, 1987 3. Bonney WW. Robinson RA. I.achenhruch PA, et al: Yield of. cancer tissue from prostatic needle biopsy. Urolo~ 29: 153- 156. I987 4. Agatstein EH, Hernandez FJ. I.ayfield LJ. et al: Clsr of fine needle aspiration for detection of stage A prostatic cal-cinema befol-e transurethral resection of the prostate: A clinical trial. J LTI-oI 13X: .5.51-.i.53, 1987 5. McNeal JE: Normal histology of the prostatr. .4m J Surg Pathol 12:6 1o-ti33, 1988 6. McNeal JE. Reclwine LA, Freiha FS, ct al: Zonal distribution of pl-ostatic adenocar~inorna: Correlation with histologic pattern and direction of spread. Am J Surg Pathol I2:897-906, 1988 7. Reese JH. MrNeal JE. Redwine EA. et al: Tissue type plasminogen activator as a marker fox- functional zones within the hutnan prostate gland. Prostate 12:47-53, 1988 8. McNeal JE: Morphologic indices of progrrssion in prostatic carcinoma, in Coffey IX, (Ltrdner WA, Bruchovsky N, et al (eds): Curr-ent Concepts and Approaches to the Study of Prostate (:ancrr. New York. NY, Liss. 1987. pp 779-782 9. Breslow M. Ghan CW. Whom G, et al: I,atent carcinoma of prostate at autopsy in seven areas. Int J Cancer 20:680-688. 1977 10. Franks LM: Latent carcinoma of prostate.,J Pathol Bactrriol 68:603-610. 195-l 1 1. Foulds I.: The exper-imental study of tumour progl-ession: A review. Cancer Res 15:327-339. 19.54 12. Paste G, Grieg R: On the genesis and regulation of cellular heterogeneity in malignant tumors. Invasion Metastasis 2: 137-l 76, I982 13. Fidler IJ. Hart R: Biologic diversity in metastatic nroplasms: Origins and implications. Science 217:998-1003. 1982 11. McNeal JE, Bostwirk IX, Kindrachuk RA, et al: Patterns of progression in prostate cancer. Lancet l:(iO-63, 1986 Ii. Broders AC: Carcinoma. Grading and practical application. Ar-ch Pathol 2:376-38 I, 1926 16. Murphy GP, Whitmore WF: A report of the workshops on the curl-em status of the histological grading of prostatic cancer. Cancel 44: 1490-l 494, 1979 17. Mostofi FK, Sesterhenn IA. Sohin IH: International Histological Classification of Prostate Tumors. Geneva. Switzerland. World Health Organization. 1980 18. Gaeta JF, Asirwatham JE, Miller G. et al: Histological grading of primary prostatic cancer: A new approach to an old problem. .J Ural 123:689-6x3, 1080 19. Brawn PN. Avala AA, Eschenbach AC, 1-t al: Histologjcal grading and study of l&static adenocarcinoma: Development of a new system and comparison with other methods. Cancrr -19: I 13-190. 1982 20. McNeal JE, Villiers A, Redwine EA. et al: Microcarcinoma of the prostate: Its association with duct-acinar dysplasia. HLIMPATHOI 22:644-652, 1001 2 1. Paget J: The distribution
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of