Atypical adenomatous hyperplasia of the prostate: Morphologic criteria for its distinction from well-differentiated carcinoma

Original Contributions Atypical Adenomatous Hyperplasia of the Prostate: Morphologic Criteria for Its Distinction From Well-differentiated Carcinoma DAVID G. BOSTWICK, MD, JOHN SRIGLEY, MD, DAVID GRIGNON, MD, JOHN MAKSEM, MD, PETER HUMPHREY, MD, PHD, THEODORUS H. VAN DER KWAST, DEBASHISH BOSE, BS, JAY HARRISON, MS, AND ROBERT H. YOUNG, MD adenomatous

Atypical

hyperplasia

(AAH)

of small glands within

the prostate

cinoma.

the diagnostic

from

To determine

carcinoma,

lected

lesions

patterns

seven observers

from

association differentiated tologic

(eight

evaluated,

these three patterns: respectively),

hyperplasia:

of uncertain

carcinoma

features

variation

largest

loids within luminal absence

suspicious

nucleolar

infiltrative (compared

1.66 wm, 2.71 greater

348El2

membrane

in AAH

(compared

immunostaining), with

from carcinoma

borders,

anti-keratin in carcinoma;

Features that could

included

lesion

average gland size, variation

size and shape, nuclear shape, chromatin

dis-

and intact basement

discontinuity

immunostaining).

multifocality,

than

crystal-

with complete

shown with basal cell-specific

antibody

separate AAH

and cy

(16%, 13%, and 75%, respectively), secretions,

monoclonal

not reliably

(mean,

of nucleoli

pattern,

Copyright

appearance

significance and immu-

from carcinoma

in most

‘Cm1993 by W.B. Saun-

Company

Small glandular proliferations in the prostate form a morphologic continuum ranging from benign proliferations with minimal architectural and cytologic atypia to those in which the degree of atypia is such that they are easily recognized as well-differentiated adenocarcinoma. The proliferations are distinguished easily at widely spaced points of the spectrum; however, no abrupt changes are apparent along the continuum. Lesions with a degree of atypia that raises the possibility of carcinoma recently have been the subject of much interest. Despite this, criteria for their clear separation from cancer are not firmly establishetl. &awn noted that there were “no absolute histologic criteria to separate these two entities,“’ and some of his photomicrographs of severe adenosis were subsequently interpreted by others to be carcinoma.“-” Another investigator’s’ photornicrographs of well-differentiated carcinoma were consiclered by one reviewer as “suspicious by all perhaps, certain by few.“” Murphy wondered “if‘interlobular acinar carcinoma can be recognized at all. “’ Additional problems associated with at),pical adcnomatous hyperplasia (AAH) concern (he extent to \vhich it has, or does not have, premalignant features. Circumstantial evidence supports the validity of AAH as a precursor lesion or marker for prostatic adenoc~~I-cirloIll~l. ‘.‘-“’ However, follow-up studies are needed to demonstrate the natul.al history of these lesions and to determine optimal patient management. Such studies require standardizecl lerminology and criteria for identifying these lesions. II is apparent from pre\ious reports that such standardization does not exist. To define strict morphologic criteria for distin@shing AAH from well-ditierentiated carcinoma, seven pathologists indepenclently evaluated various light microscopic features in 54 lesions frc 111144 transurethral

(eight foci), and well-

(0.69 Fm, 1.43 pm, and 1.78

of the basal cell layer in AAH

circumscription,

ders

were useful in separating

percentage

glands

shown with type IV collagen

Three

(38 foci), atypical small

diameter

the biologic

allow it to be distinguished

cases. HUM PATHOL 24:819-832.

in

Although

its light microscopic

54 se-

all arising

Of 24 architectural

quality of cytoplasm. is uncertain,

nophenotype

in nuclear size (14%, 22%, and 25%,

mutinous

in carcinoma;

of AAH

AAH

specimens.

(17.6%, 58.1%, and 77.5%, respectively),

basophilic

continuity

foci).

diameter

pm, and 2.81 pm, respectively), 1 pm in diameter

AAH

for car-

evaluated

observed,

significance

the following

mean nucleolar

pm, respectively),

resection were

tinctorial

proliferation

for separating

independently

proliferation

with nodular

acinar proliferation

criteria

44 transurethral

of glandular

is a localized

that may be mistaken

MD, PHD,

shape, in gland

and amount and

819

Volume 24, No. 8 (August

HUMAN PATHOLOGY

1993)

FIGURE 1. Atypical adenomatous hyperplasia. (Top) This solitary circumscribed cluster oi small glands was present in an area of nodular hvoerplasia. (Bottom) At high magnificdiion, the nuclei are uniform and round with inconspicuous nucleoli.

resection

specilnens.

Immunohistocl~e~nical

stains

MATERIALS

tli-

rected at the prostatic basal cell layer (basal cell-specific anti-keratin monoclonal antibody 34/3E12) and basement membrane (anti-type IV collagen) were compared with the light microscopic findings. Our results suggest that the combination of architectural, nuclear, nucleolar, and immunohistocheInica1 features allows identification of AAH and accurate separation from adenocarcinoma in most cases.

AND METHODS

Light Microscopic

Study

Seven p;~thologists I~ronl institutions in the United States, and the Netherlands participated in this study. Slides and hloc.ks of’ tissne f’rom the archives and consultation files of the differrnt hospitals were contributed for exchange and rcvicw. Tissues obtained front transurethral resections of the prostate (virrually all consisted of tissue from the periurethr;ll area and transition ~onc) were fixed in IO% buffwed f’ormalin, Ch~atla,

820

AAH OF THE PROSTATE

(Bostwick

et al)

FIGURE 2. Atypical adenomatous hyperplasia. At the periphery of this nodule the glands are small and tightly packed. At high magnification (bottom) the nuclei are uniform and nucleoli are inconspicuous.

to evaluate each focus. The diagnose werr niatle without pi-ioidiscussion among the participants. Twenty-Cour architeclural mtl cytologic features werr evaluated, iilcluding circ uniscrip tion, infiltrative borders (irregulairagged borders), lesion asyniiiieti~, multifocality, average gland siLe. \Gatiotl in gland size and shape. chromatin pattern, variation iii nuclear hiLr antI shape, amount and tinctorial quality of cvtoplasni, and cr\~stalloids. the presence of cc,~-poi-a aniylacea arc1 luin&l One observer (D.G.B.) measured 200 nuclc>i from each focus by ocular micrometer at X640 on a Nikorl Optiphot microscope. The following were quantitated: mean nriclrolar diameter, largest nucleolar diameter. and percentage of nuclroli

processed routinely, and embedded in paraffin. Cases were selected that contained focal atypical glandular proliferations within the prostate diagnosed as adenosis, sclerosing adenosis, AAH, or well-differentiated carcinoma (Gleason primary grade 1 or 2). All the patients were older than 50 years, and transurethral resection of the prostate was undertaken because of obstructive symptoms clinically attributed to nodular hyperplasia. Data on serum levels of prostate-specific antigen were not available. One set of coded slides was stained with hematoxylineosin and reviewed independently by each of the participants without knowledge of the clinical history. Observers werr asked

821

HUMAN PATHOLOGY

Volume 24, No. 8 (August

1993)

adeFIGURE 3. Atypical nomatous hyperplasia. These glands were part of a solitary localized cluster of small glands embedded in a sclerotic stroma. The nuclei are slightly enlarged and nucleoli are inconspicuous.

~rrater

than

including

1 pm

noduh

in

cliaineter.

Asscxiared

khions

wt’rt‘ noled,

hyperplasia,

high-grad’ proatalic intraeprhelial neoplasia, and inflamniation. Two C~SC~of atroph) as deterniined Iq the seven observers (935% (,oI~~oI-da11c.e) wei.? excluded previously.

diatneters > I pi) 01 cacrgot-ical variables (q, O%, 25Y0, 50%, 75%. ;ittd 100%; sttiall, tttcdiunt, and large; etc). For c,ottrittuous variables ordinary F tests were used to dc‘tcrttiiiie whether there wcrc significant location differences among

the

hrec

~xqx<ions. To Ilvrf’ornl individual

cornpar-

iaons lw~ween groups,

lmmunohistochemical

Study

Five tttic.rotneter-think

sectiotts WCIX‘prep;~t-etl front fat-nialin-fixed, I’;lra~li-emhedtlt’d cliagtioslic tissue. ISecausC of hilcd the small size of the lesions, deeper sections frequelltlj to disclose diagnostic tissue, and these cases could nol be ebaluated by it~~tiiunoltis~o~hetni~al staining. Twenty-three cast3 contained tissue suf’fificient for imtiiu~ioltisto~~ieitti~~t~ studv. The aridin-biotin-~otttl)lex itnmitnopet~oxicl~se techttiquc (i’CClC>l I,aboratories, Burlittgatne, <:A) was usccl with Iwo Iltonoclonal antibodies to evaluate immuttoreactivity for basal cell-specific keratin (Enm Biochemical, New York, NY; high moleculat weight keratin clone, 34PEI 2) and type IV collagen (courtesy of Dr Michael Havenith, The University of Maastricht, The Netherlands), as previously described.‘,‘.” Normal prostatic tissue served as a positive control; substitution of primary attibodies with normal mouse seruni served as a ttega:ative control.

Statistics Statistical analyses were undertaken to clc~c~rtnine which factor or cotnbination of factors was useful itt distinguishing between AAH, atypical sniall acinar proliferation of uncertain significance. and well-difleretttiated carcinoma. Four ditferettt cotnbinarions of these three diagnostic groups were analyzed: (1) carcinoma versus AAH versus atypical stttall acinar proliferation, (2) AAH versus atypical srrtall acinar proliferation, (3) AAH and atypical stnatl acinar proliferation versus carcitto~na, and (4) atypical s~nall acinar proliferation v~~w_ts carcinonla.

Thr light microscopic- features wcw attatyzed by different statistical tests based ott whether- they were contitiuous \ariahles (ungt-ouped nutneric values; these i&luded lesion size, largest tiucleolar diatneter, average nucleolar cli;itttetet-. aiitl tttideotat

822

SclieRe c~ottfidettcr intervals”’ were used 10 pt~o\itle c.otiser\ati\e estitttates that were consisten( with the itt~erval fot- a certain comparison did F tests. If the co~tfitlence not ittcltitle /era, iI was ittferred that the groups under coniparisott werr significantly difltrettr. Cotificlencc intervals wcrc’ constrticred ;I( the !I.:,% level. FOI. nonCnJ c;ttegoric.:il variables the two-tailed Fisher’s rxac’t test was used lo cotttpare the levels of discrete variables xnc~ng diagnostic groups. FOI. ordinal categorical variables rhr Kruakal-M’allis test was usrd.

RESULTS Fifty-four foci from 44 transurethral resection specimens were evaluated. All foci consisted of small glandular proliferations suspicious for well-differentiated aderloc;lrcinoIna. One focus was seen in 35 specimens, two foci in eight specimens, and three foci in one specimen. The final study diagnosis for each focus was based on the majority (four or more) of responses from the seven participating pathologists. Criteria fol entry into the category of atypical small acinar proliferation of uncertain significance were concordance for a diagnosis of “suspicious but not diagnostic of carcinoma” (two foci) or significant lack of diagnostic concordance (six foci had less than four concordant diagnoses that ra~lgecl from AAH to cancer, and these were included in the category of atypical small acinar proliferation). Using these criteria 38 foci were considered to be AAH (Figs 1 to 3), eight foci were atypical small acinar proliferation of uncertain significance (Figs 4 to (i), and eight foci were carcinoma (Fig 7).

AAH OF THE PROSTATE

(Bostwick

et al)

FIGURE 4. Atypical small acinar proliferation of uncertain significance. (Top) At the periphery of this nodule in the transition zone, circumferential streaming small glands are seen. (Bottom) Despite mild nuclear enlargement, the chromatin pattern is uniform without significant nucleolar enlargement.

Interobserver

Concordance

Overall (.oncordance for the 378 diagnoses (54 foci diagnosed by seven observers) was 80.7%. Individual pathologist concordance ranged from 7 1.6% to X7.5%. Atypicd Ad~nomatous Hypuplmia. Concordance ~OI AAH was 88.0%. Alternative diaLmoses included atypical small acinar proliferation of uncertain significance (6.7%), hyperplasia (4.8%), and atrophy (0.596). There was agreement among all observers in 16 of t tie 38 foci (4L’.l9%), among six of seven observers in 13 of the foci 823

(33.2%), ;iiiior~g fi\,e of seven ohservers in seven of the fi)ci (18.4%), and among fout- c~f’s~vcn observers iti two of Ihc foci (5.:3%). .?I_y/~iutl

Stttcill

d4c,itulr

.Sigtt{ficcctrw. (~onc~ordanc~

Prolifrtxtintl

of

L~‘ttwrtctitt

f’or Iitypical s~itall acinar proliferation \~as 11 I Yc. Alternative diagnoses inc.ludcd AAH (:S!J.S%) and \~,ell-difl’erc~ntiatetl carcinonia (I !I.(ic%~). There was agreement among five of sr\en ohser\~et-s in one of‘ the l’oci (1 :‘.5Yo), among four of scvcti otlservcrs in one of (tic f’oci (I 2.5%‘),

HUMAN PATHOLOGY

Volume 24, No. 8 (August

1993)

FIGURE 5. Atypical small acinar proliferation of uncertain significance. The glands are small to medium sized, predominately circumscribed, with darkly staining nuclei and inconspicuous nucleoli. The variation in gland size and focal lack of circumscription architecturally were considered suspicious for carcinoma despite the absence of significant cytologic abnormalities.

among three of seven observers in two of the foci (25.0%), and among two of seven observers in four of the foci (50.0%). Carcinoma. Concordance for well-differentiated carcinoma was 87.5%. Alternative diagnoses included AAH (3.6%) and atypical small acinar proliferation of uncertain significance (8.9%). There was agreement among all seven observers in five of the eight foci (62.5%), among five of seven observers in two of the foci (25.0%), and among four of seven observers in one of the foci (12.5%).

Architectural

and Associated

Features

The size and asymmetry of foci of AAH, atypical small acinar proliferation of uncertain significance, and well-differentiated carcinoma were not significantly different, with a wide range in size for all lesions (Table 1). Atypical adenomatous hyperplasia was more likely to have infiltrative borders; however, five of the eight cancers were Gleason primary grade 1 pattern, which by definition have little or no infiltration.” Atypical adenomatous hyperplasia tended to be more multifocal than either atypical small acinar proliferation of uncertain significance or cancer, but the differences were not significant. Average gland size and variation in gland size were similar for all three lesions. There was a suggestion of greater variation in gland shape in AAH, but the differences were not statistically significant. Most of the lesions in our study (100% of foci of AAH and atypical small acinar lesions of uncertain significance, and 87% of foci of carcinoma) were observed in the periurethral area and transition zone in intimate association with nodular hyperplasia, usually occurring within a hyperplastic epithelial nodule or within 1 medium power field of a nodule (Nikon Optiphot micro-

scope, Xl 00). This may retlect the exclusive use of transurethral resection specimens in our study. Some nodules showed partial involvement by the small glandular lesion, usually at the periphery, whereas other nodules consisted entirely of small glands, particularly with AAH. High-grade prostatic intraepithelial neoplasia was observed in association with 38% of cancer foci, greater than that observed in AAH and atypical small acinar proliferation of uncertain significance (16% and O%, respectively), although the differences were not significant. Patchy chronic inflammation was frequently observed, with no significant differences among the three groups. Sharp-edged, refractile eosinophilic luminal crystalloids were seen in most of the foci of carcinoma (75%), significantly greater than the frequency found in AAH and atypical small acinar proliferation (16% and 13%, respectively). Conversely, the frequency of corpora amylacea did not differ significantly among the lesions (see Table l), although there was a greater frequency in AAH. Although not quantitated, basophilic lumenal mutinous secretions appeared more frequently in carcinoma than in AAH or atypical small acinar proliferation of uncertain significance. When case frequency was compared with which hospital submitted the case, no differences were found (I’ > .05).

Cytologic

Features

There was a significant diflerence in nuclear size variation between AAH, atypical small acinar proliferation of uncertain significance, and cancer, largely because of the effect of AAH (Table 2). Conversely, nuclear shape variation did not differ significantly among the groups. The chromatin pattern was usually uniform and finely punctate in all three lesions, with no differences observed. Nucleolar size was considered inconspicuous

824

AAH OF THE PROSTATE

(Bostwick

et al)

FIGURE 6. Atypical small acinar proliferation of uncertain significance. (Top) This irregular small glandular proliferation at the periphery of a benign nodule was accompanied by a cellular sclerotic stroma. (Bottom) Occasional small nucleoli are observed, but are not prominent.

in AAH, somewhat prominent in atypical small acinal proliferation, and prominent in carcinoma; this criterion was considered by all observers as most inlportant in separating these lesions. All three measures of nucleolar size (largest nucleolar diameter, mean nucleolar diameter, and percentage of nucleolar cliameters > 1 /.LIII)showed significant differences between A.4H, atypical small acinar proliferation, and cancer. Although there was overlap in the ranges of nucleola~ diameters, the means and medians of each showed a

progressive increase from AAH lo at)F)ical small aciliar proliferatioli and cancer. M7ien atvpical small aciniir prolifcmttion of uncertain significancr alone was c~oniparcd with cancer, the differenc~t~s were 1101 significant. The statistical results should be interpreted with caution. The \,alidity of the confidence intervals increases with sannple size; with onl! eighl ohservatioris in the assumptions necessark mch of two of the groups, for the statistical procedures cannot hc \~erified. In ou;. 825

HUMAN PATHOLOGY

Volume 24, No. 8 (August 1993)

sZ.>“ f (,_

:..+=+-.*~~

---

:

a

‘.

(-;’ ( *

study estimates were based within the AAH group. lmmunohistochemical

largely

on

;:

FIGURE 7. Adenocarcinoma, Gleason primary grade 1. (Top) This small glandular proliferation is uniform and circumscribed. (Bottom) There is nutYear enlargement and prom1inent nucleolar enlargement, with occasional crystalloids I:bottom right).

uous keratin-immunoreartive basal cell layer, varying from being 20% to 50% fragmented (Fig. 8). Two cases of atypical small acinar proliferation of uncertain significance were evaluated, and both showed a fragmented basal cell layer (20% and 90% fragmented). Three cases of well-differentiated adenocarcinoma were evaluated, and all showed absence of basal cell staining (Fig. 8). Nonimmune normal mouse serum (negative control) produced no staining. Type IV collagen immunoreactivity was most intense around small and medium-sized blood vessels and

observations

Findings

Normal prostatic glands displayed intense cytoplasmic immunoreactivity for keratin 34/3E12 in virtually 100% of basal cells, forming a continuous or near-continuous layer at the periphery of the glands; some disruption was seen in inflamed glands. Nine cases of AAH were evaluated, and all showed a fragmented discontin826

AAH OF THE PROSTATE

(Bostwick

et al)

FIGURE 8. lmmunohistochemical staining with basal cell-specific antikeratin 34flE12. (Top) Atypical adenomatous hyperplasia displays a fragmented discontinuous immunoreactive basal cell layer. (Bottom) The complete absence of an immunoreactive basal cell layer in adenocarcinema (left) with adjacent benign prostatic glands (right) serving as an Internal positive control.

IV collagen-immunoreactive fibers were greater with AAH than with adenocarcinoma (Fig. 9); seven of nine cases of AAH and three of three cases of atypical small acinar proliferation of uncertain significance displayed delicate immmloreactive fibers representing apparent basement membrane completely around glands, whereas two of nine cases of AAH and three of three cases of adenocarcinoma displayed discontinuous and incomplete staining.

also displayed moderate to intense staining around smooth muscle throughout the stroma. Moderate staining was seen at the periphery of all prostatic glandular nodules, including usual nodular hyperplasia, AAH, atvpical small acinar proliferation of uncertain significance, and carcinoma. Epithelial basement membrane staining at this site could not be distiqguished with certainty from stromal staining. Centrally within the glandular proliferations, the number and intensity of type 827

HUMAN PATHOLOGY

Volume 24, No. 8 (August

1993)

FIGURE 9. lmmunohistochemical staining with anti-type IV collagen. (Top) Atypical adenomatous hyperplasia displays immunoreactive basement membrane surrounding many of the glands centrally, as well as scattered small blood vessels and the surrounding muscular stroma. (Bottom) The central portion of the focus of adenocarcinoma shows few immunoreactive fibers.

DISCUSSION

those that meet the criteria for well-differentiated adenocarcinoma of the prostate (Gleason primaly patterns [grades] 1 or 2 out of 5). That this is a common problem is not surprising given the fact that the incidence of AAH varied from 19.6% in transurethral resection specinlens’H to 24% in an autopsy selies of men in the second through fourth decades of life.“’ Our results indicate that AAH is distinguished from well-differentiated carcinoma by the following: (1) in-

The interpretation of problematic small acinar lesions in the prostate gland is one of the most frequent and most challenging encountered in surgical patholoby practice. It was the purpose of this study to define criteria that could be used in the distinction of benign processes falling in the category of what has been referred to in the literature as “atypical adenomatous hyperplasia” or “adenosis” and

828

AAH OF THE PROSTATE

TABLE 1.

Comparison Between Atypical Adenomatous Hyperplasia and Well-differentiated Carcinoma: Architectural and Associated Features

AAH (n = 3X) \I-chitectural features I.esion si,e (nm?) Avrragc Median Kangc Standard deviation I.esion asymmrtty* Infiltrative horde19 (+, f, -) Multifocalit\ Average gland sirr (small, medium) Variation in glxid siLe: Variation m g:land shape: .\swciated fratures High-grade PIN§ Inflammations Crystalloids (:orpora amylacea

(Bostwick et al)

Atypical Small AcinalProliftration of Uncertain Significance (n = 8)

(:arcinom.t 1, AAH ?I At) pical Small Arinat Prolifcl-ation of Uncertaitl Significantr (P)

Welldifferentiated Carcinoma (n = 8)

AAH 1~ Atvpical Small Acinar t’rolifer~ation of Llnccr-tain Significance

Ar\pical Small Acinar PI-oliferaiion 01 Llncertaiu Significante II (:;u-cinema (( :onfidenct Interval)

(Corrfidtwe

Iriter\al)

2.50 2.00 O.Y”-8.00

‘2.5;

N.CN

NS

.:33 (NS) .32 (NW

NX

NS

NS N>S

NS NS

.(iS (KS)

NS

N5,

NS

.oi

NS

IJ.Oi

NS

,001

0%’ 5OY@ 13% 0%’

Abbreviations: NS. not significant (P > .0.3; PIN, pwstatic * 0, round, symmetric; 1 OO%, asymmetric. t Kruskal-Wallis probability. : Graded on OR,, 25%. 50%, 75%, IOO% scale. 5 Within 1 loti powrr field (X40).

NS

.50 (NS)

25% 0. lOO%, 0

It

(NS)

.I J (NS) .5X (NS) .oo I .I2 (N’s) intraepithrlial

conspicuous nucleoli, (2) infrequent crystalloids, (3) lack of basophilic mucin, and (4) fragmented basal cell layer as seen with basal cell-specific anti-keratin antibodies (Table 3). Despite the utility of these features, the absolute distinction between AAH and carcinoma is still problematic in some cases (see below). We found that all measures of nucleolar size allowed separation of AAH from adenocarcinoma, including mean nucleolar diameter, largest nucleolar diameter, and percentage of nucleoli greater than 1 pm in diameter. The level of interobserver concordance (80.7%) was higher than expected, considering that the participating pathologists did not discuss diagnostic criteria before undertaking the study; afterward, all agreed that nucleolar size was the single most useful feature. Such concordance is probably due to widespread acceptance of Gleason’s criterion of nucleolar diameter greater than 1 ~111for separating well-differentiated cancer (Gleason primary grades 1 and 2) from other proliferative lesions.” It is interesting to note that micrometer-based measurements of nucleolar size were available to only one of the pathologists (D.G.B.), and none used morphometry in reaching a final opinion, relying instead on individual (subjective) evaluation and experience. Concordance of individual pathologists with group diagnoses ranged from 71.6% to 87.5%.

ncoplasia.

Nucleoli are found in virtually all cells but are not usually considered “prominent” or enlarged in the prostatic epithelium until they measure greater than 1 .O to 1.5 pm in greatest dimension in routine formalinfixed sections. The prognostic significance and diagnostic usefulness of nucleolar area and size in prostatic carcinoma have been demonstrated by various methods, including scanning electron microscopy”” and computerized image analysis.“-“’ Tannenbaum et al’” found that nucleolar diameter was a powerful discriminant of cancer when compared with benign prostatic epithelium. Hoda and Reed” showed that nucleoli in AAH were intermediate in size between nodular hyperplasia and well-differentiated adenocarcinoma ancl that only cancer had two or more nucleoli in an individual cell. Similarly, Keleman et al’” found that nucleolar prominence separated AAH from carcinoma; however. they considered a nucleolus prominent when the diameter was 3 pm or greater, considerably larger than that observed by Rocking et alY4 (1.88 pm), Gleason” (1 pm), Tannenbaum et al”’ (2.4 ym’ surface area), Deschenes and Weidner’” (AAH, 0.79 pm; Gleason grades 2 and 3 cancer, 1.60 pm), and Montironi et al,” as well as by us. Conversely, Layfield and Goldstein’” failed to find any nucleoli more than 1.8 pm in diameter in benign or low-grade mali 5. nant fine-needle aspirates. Interestingly, Keleman et al-” 829

HUMAN PATHOLOGY TABLE 2.

Comparison

AAH (n = 38) Variation in nuclear size* Variation in nuclear shape* I.argest nucleolat diameter (fitn) Mean Median Range Standard deviation Mean nucleolat diameter (jmi) Mean Median Range Standard deviation Nucleolar diameter > 1 /ml

Mediate Range Standat-d

Between Atypical Adenomatous Hyperplasia and Well-differentiated Carcinoma: Cvtoloaic Features

Atypical Small ArinatProliferation of Uncertain Significancr (11 =

8)

Carcittonta u .\AH v Atypical Small Acinar Proliferation of Uncertain Significance

Welldifferentiated Carcinoma (11 =

8)

(6

AAH u Atypical Small A&tat Proliferation of Untertain Significance (confidence

Interval)

AAH and Atypical Small Acinal Proliferation of Uncertain Signifiranc c ((;ombined) u Carcinoma (<:onfidcnce Interval)

Atypic al Small Acinar I’roliferatiott of Lltrcertain Significant e 7) Ckxinoma (Confidence Interval)

14%

‘22YG

25%

.Ol!)

NS1_

NSt

NSt

14%

19%

22%

NS

NC-+

NSt

NSt

1.001

-1.57. -0..:3

-1.17, -0.08

NS

<.oo 1

~

1 .6tj

?.71

2.81

‘L.85 2.0-3.0 0.3ti

3.00 2.5-3.0 0.26

I .49

1.78

1.50

1.85 1 .o-2.5 0.45

0.7-2.0 0.48

58. I ‘%

Mean

Volume 24, No. 8 (August 1993)

I .08, -0.3’)

57.596

deviation

Abbreviation: NS, not significant (I’ > .05). * Graded on OYO,25Y0, 50Y0, 7596, 1 OOW scale. t Two-tailed Fisher’s exact test.

also found no significant difference in nucleolar diameter between AAH and normal and hyperplastic epithelium. Various other morphologic features were not useful in distinguishing AAH from adenocarcinoma, including lesion shape, circumscription, multifocality, average gland size, variation in gland size and shape, chromatin pattern, and the amount and tinctorial quality of the cytoplasm. Immunohistochemistry also is valuable in the diagnosis of AAH. Our study showed that the basal cell layer is characteristically discontinuous and fragmented in AAH, a feature that can be demonstrated immunohistochemically with basal cell-specific anti-keratin 34PE12 to separate AAH from carcinoma; these results agree with those of others.“~‘4~2”-9’ The type IV collagenimmunoreactive basement membranegg appeared to be normal in AAH and decreased in carcinoma, although this was a difficult feature to evaluate due to the intense stromal and vascular smooth muscle immunoreactivity. Other phenotypic markers also may be of value in separating AAH from carcinoma, such as acid mucin stains”l.s4,:4n; however, acid mucin is not specific for malignancy.‘44 There is no standard terminology for the small glandular proliferations of the prostate that we refer to 830

as “atypical adenomatous hyperplasia,” and consensus may be difficult to reach until more is known of their prognostic significance. We recommend this term but recognize that there is a morphologic spectrum of small glandular lesions culminating in well-differentiated adenocarcinoma. The greatest difficulty in distinguishing AAH from carcinoma is with lesions containing nucleoli intermediate in size between benign and malignant.” To accommodate the uncertainty of this borderline group, we recommend the noncommittal term “atypical small acinar proliferation of uncertain significance, not further classified” to categorize these lesions. It should be noted that the borderline group of cases caused considerable discordance among observers in our study, and consensus could not be reached regarding its biologic significance. All agreed that further study of this subset of small acinar lesions is needed. Histologic mimics of AAH include simple lobular atrophy, postatrophic hy erplasia, sclerosing atrophy, %i.,P ‘, basal cell hyperplasia, atypIcal basal cell hyperplasia,“’ and metaplastic changes associated with radiation, infarction, and prostatitis. Many of these mimics can display architectural and cytologic atypia, including INcleolomegaly; thus, caution is warranted in the interpretation of scant specimens, cauterized or distorted

AAH OF THE PROSTATE

TABLE 3. Diagnostic Criteria for Atypical Adenomatous Hyperplasia (.arcinoma

I

(:ircutnscrihed

<:ircunwrihed

Prlshirigj

Pushing,/

infiltr.ative Ixsion

ai/c ,mtl

and

2)

irrtiltratiw

\‘arial)le

\:ari,lhlc

ilsynllllrlr~ (;land

si/c

(%md

shape

variation

Variable

lacea

Frequent

(:rvstalloidst Corpol-a

Variable

variation

Infrequent ml)

Basophilic

(nwc

inc,un)

(165%) (?I?%)

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malignant lesion of the prostate because of the following: increased incidence in association with carcinoma (15% in 100 prostates without carcinoma at autopsy and 3 1% in 100 prostates with cancer at ;rutopsy),‘.s,“‘,“‘.~~ topographic relationship with small-acinar carcinoma,‘.‘” age peak incidence that precedes that of carcinoma,’ increasing silver-reactive nucleolar organizer region count,“‘.” increased nuclear area and diameter,‘“’ and a proliferative cell index that is similar to that of small acinar carcinoma, but significantly higher than that of normal atnd hyperplastic prostatic epithelium.47 Brawn showed that cancer developed in seven of 108 patients with AAH (6.5%) within 5 to 15 years, compared with X4 of 2,263 patients with hyperplasia (3.7%), although no “absolute” criteria were identified to separate his cases from carcinoma.’ Conversely, some investigators claim that the link between cancer and AAH is an epiphenomenon and that the data are insufficient to conclude that AAH is a premalignant lesion.‘” It also has been suggested that AAH may be related to the subset of cancers that arise in the transition zone in association with benign prostatic hyperplasia.lX Although the biologic significance of AAH is uncertain, its light microscopic appearance and immunophenotype allow it to be separated from carcinoma in most cases. Our study has attempted to define the diagnostic criteria along the morphologic continuum of small aciIMI‘ lesions to allow for valid comparisons among different observers. We believe that when AAH or atypical small acinar proliferations of uncertain significance are encountered in prostatic specimens, all tissue should be embedded and made available for examination; serial sections of suspicious foci may be useful. Unfortunately, needle biopsy specimens and cytologic specimens frequently fail to show the suspicious focus on deeper levels, confounding the diagnostic dilemma. The identification of AAH or atypical small acinar proliferation of uncertain significance should not influence or dictate therapeutic decisions; however, the clinical importance of these lesions is not understood, and close surveillance and follow-up appear to be indicated. *”

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specimens, and specimens submitted with incomplete patient history. Atypical adenomatous hyperplasia may be associated with sclerosis, but further study is needed to determine the relationship between this lesion and sclerosing adenosis,:~“~:~‘~““~“’ Sclerosing adenosis differs from AAH by a striking myoepithelial metaplasia of the basal cell compartment as well as an exuberant stroma composed of fibroblasts and loose ground substance. The basal cells in this condition show positivity for S-100 protein and muscle-specific actin and demonstrate thin filament collections and dense bodies on electron microscopy,~“.:lo,“l.~~ This immunophenotype is unusual in the prostate because normal prostatic basal cells do not demonstrate myoepithelial differentiation; consequently, most investigators believe that sclerosing adenosis is a form of metaplasia.“‘~“l~““~~4~~4~~‘~:~

REFERENCES I.

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IZdcnosis

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49:826-835,

I982

Atypical adenomatous hyperplasia also should be distinguished from lobular atrophy and postatrophic hyperplasia. Both lesions tend to have a low-power lobular organization. Simple atrophy consists of shrunken glands that demonstrate strong basal cell-specific keratin positivity. Postatrophic hyperplasia may cause difficulties, since proliferating luminal cells with small amounts of clear cytoplasm may be seen in an atrophic background. These cells may demonstrate some degree of cytologic atypia and luminal mucin may be identified, but strong basal cell-specific keratin staining usually is maintained, in contrast to AAH, in which a fragmented pattern is usually seen. Is AAH a precursor of adenocarcinoma! Atypical adenomatous hyperplasia has been proposed as a pre-

2. (ed):

Kost\\ic

klthl)h)~T

Iwo,

SI-igle) Proctatc.

the

J:

Pt~emalignarrt

NcwYoI.~.

Icsions. NI’.

in

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pp 37.59

5.

Epstein

JI:

Itrterpr-ctation. 6. Surg

7.

S:

PA, Kobi

(.llo(.ill.(.itiotIld

Prostatic WM.

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8.

York,

NY,

in Kpstcirl,jl Kwen,

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(e(l):

1089,

pp 99-1

interprrtation

Prostate

Kiops)

12

(hook

rrvirw).

Am

J

15:%3, 199 1

Murphy

delphia,

Adeno~arrinonla,

Nrw

Kosen

Path01

wrninal

831

k I)(;, of

in

&eta

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1089,

Mic-rowq~ir of

JF:

Murphy

pwstatr.

I)ivzasrs

of

WM

(ed):

Urologic

pp

147-2

differential Pathol

Annu

the

prostate al

gland

Pathology.

and Phila-

I8 diaynosis L’O:

of

small

xirrar

157.17!).19X5

ad-

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