Mucin expression in atypical adenomatous hyperplasia of the prostate

Mucin Expression in Atypical Adenomatous Hyperplasia of the Prostate NEAL S. GOLDSTEIN, MD, JUNQI QIAN, MD, AND DAVID G. BOSTWICK, MD Prostatic atypical a d e n o m a t o n s hyperplasia (AAH) is a small glandular proliferation that has histological similarities with well-differentiated adenocarcinoma. To determine the histochemical profile of AAH, we assessed the production of total neutral mucin, total acidic mucin, and sulfated acidic mucin in 24 cases of AM-I, five cases of Gleason primary pattern 1 and 2 adenocarcinoma, and 29 cases of a d j a c e n t benign and hyperplastic prostatic tissue. All specimens were formalin-fixed transurethral resections, and the diagnosis in each was confirmed by evaluation of the keratin 34B-E12 immunoreactive basal cell layer (intact in benign and hyperplastic epithelium, fragmented in AAH, and absent in cancer). The extent of mucin staining was measured semiquantitatively in 10% increments a c c o r d i n g to the number of stained glands. Neutral mucin was found in all but two cases, a n d t h e r e w a s n o apparent difference in the amount of staining in benign glands, AAH, and cancer (mean number of stained glands, 43%). Total acidic mucin w a s m o r e c o m m o n in AAH (63% of cases; mean, 11% of glands) and adenocarcinoma (60% of cases; mean, 30%

of glands) than in benign glands (0% of cases). Similarly, nonsulfated acidic mucin was m o r e c o m m o n in AAH (63% of cases; m e a n , 12% glands) and adenocarcinoma (60% of cases; mean, 8% of glands) than in benign glands (0% of cases); the p a t t e r n a n d intensity of staining for nonsulfated acidic mucin appeared to be similar to that f o r total acidic mucin in AAH a n d c a n c e r . These findings indicate that there is a close relationship in mucin expression between AAH a n d well-differentiated adenocarcinoma. Identification of acidic m u cin should be used c a u t i o u s l y as a n adjunct in the diagnosis of adenocarcinoma but is useful in separating s o m e cases of AAH and adenocarcinoma f r o m b e n i g n prostatic epithefium. HUM PATHOL 26:887-891. Copyright © 1995 by W.B. Saunders C o m p a n y Key words: prostate, atypical adenomatous hyperplasia, mucin, c a r c i n o m a , premalignant, sulphated mucin, benign prostatic hyperplasia, epithelium. Abbreviations: AAH, atypical adenomatons hyperplasia; PIN, prostatic intraepithelial neoplasia; AB, alcian blue.

T h e spectrum of small localized glandular proliferations of the prostate range f r o m benign to malignant. Those that are intermediate in this spectrum and usually develop in the transition zone in association with n o d u l a r hyperplasia (AAH). vll Atypical a d e n o m a t o u s hyperplasia has architectural features suggestive of low grade a d e n o c a r c i n o m a and may display worrisome cytologic features. It occurs in approximately 20% of prostates containing n o d u l a r hyperplasia, s'H T h e biological significance and diagnostic criteria of AAH have b e e n c o n f o u n d e d previously by two issues. First, AAH has b e e n c o m b i n e d frequently with other entities, including prostatic intraepithelial neoplasia (PIN), sclerosing adenosis, and atrophy, obscuring its importance. 3'6'1°'12-2° Second, a g r e e m e n t on the diagnostic criteria that allow separation o f AAH f r o m adenocarcinoma have only e m e r g e d recently. 7 Not surprisingly, the biological behavior of AAH and its relationship with a d e n o c a r c i n o m a is uncertain. Some authors believe that it is a benign lesion, whereas others believe that it may be associated with some cases of carcinoma. L2'4'8'9'2°-2~A recent r e p o r t described criteria for distinguishing AAH f r o m low-grade adenocarcin o m a based on consensus of seven pathologists evaluating various light microscopic features in 54 small glandular lesions. 6

Mucin expression in benign and malignant prostate epithelium has b e e n studied previously, 24-~3 a n d most reports identify neutral mucin in benign glands and acidic mucin in malignant glands, although benign glands rarely p r o d u c e small quantities of acidic mut i n . 24'26'28'34 Based on these findings, some have suggested that acidic mucin is a useful supportive feature in the diagnosis of adenocarcinoma, but this has b e e n refuted.27,~8,~l,3+.w In this study, we c o m p a r e d the mucin expression in AAH with that in cancer a n d benign glands, using standard histochemical m e t h o d s for neutral and acidic mucins. T h e frequency and extent of acidic mucin production in AAH and cancer were f o u n d to be similar, in contrast with benign epithelium, which contained no acidic mucin.

From the Departments of Pathology and Laboratory Medicine, William Beaumont Hospital, Royal Oak, MI, and Mayo Clinic, Rochester, MN. Accepted for publication December 1, 1994. Supported by National Institutes of Health Specialized Program of Research Excellence grant CA582254)1C. Address correspondence and reprint requests to Neal S. Goldstein, MD, Department of Anatomic Pathology, William Beaumont Hospital, 3601 West Thirteen Mile Road, Royal Oak, MI 480736769. Copyright © 1995 by W.B. Saunders Company 0046-8177/95/2608-001155.00/0

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MATERIALS AND METHODS We studied 24 cases of AAH and five cases of well-differentiated cancer (Gleason primary patterns 1 and 2) from the surgical pathology files of the Mayo Clinic and the consultation files of one of the authors (D.G.B.). All AAH cases were derived from a previous study. 6 Normal and hyperplastic prostatic tissue adjacent to AAH and cancer (29 cases) served as benign control tissues. All specimens were formalin-fixed transurethral resections for nodular hyperplasia. Atypical adenomatous hyperplasia was separated from adenocarcinoma according to published criteria, including immunohistochemical staining for basal ceils using keratin 34-BE12 as described previously (1:100 dilution with citric acid buffer-based microwave antigen retrieval; Dako Corporation, Carpinteria, CA.). 6'7 Three different types of mucin expression were evaluated as described previously.35 Neutral mucin production was determined by red staining with periodic acid-Schiff with diastase predigestion at pH 6.0 (PAS-D) but did not stain with

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TABLE 1. M u c i n Expression in Benign Epithelium, A t y p i c a l A d e n o m a t o u s Hyperplasia, a n d Well-Differentiated A d e n o c a r c i n o m a of the Prostate

Mucin Neutral Mucin

Prostate Tissue Benign epithelium Atypical adenomatous hyperplasia (AAH) Well-differentiated adenocarcinoma

Total Acidic Mucin

Sulfated Mucin

No of Cases

No of Positive Cases (%)

No of Positive Glands (mean)

No of Positive Cases (%)

No of Positive Glands (mean)

No of Positive Cases (%)

No of Positive Glands (mean)

29

29 (100%)

0-90 (43%)

0

0

0

0

24

23 (96%)

0-90 (52)

15 (63%)

0-60 (11)

15 (63%)

0-30 (8)

5

4 (80%)

0-80 (41)

3 (60%)

0-40 (30)

3 (60%)

0-30 (12)

alcian blue (AB) at pH 2.7. Total (sulfated and nonsulfated) acidic mucin production was determined by blue staining with AB, pH 2.7 (ABPAS-D). Sulfated acid mucin was determined by blue staining with AB, pH 0.7. Nonsulfated acid mucin stained blue only with AB, pH 2.7, and did not stain with AB, pH 0.7. 36 The extent of mucin staining was measured semiquantitatively in 10% increments according to the number of stained glands. The results were reviewed concurrently by the three authors and consensus was reached in all cases.

RESULTS T h e frequency o f mucin expression in benign epithelium, AAH, a n d cancer is p r e s e n t e d in Table 1. Neutral m u c i n was f o u n d in all but one case of AAH and o n e case o f cancer; there was no a p p a r e n t difference in the frequency of expression in benign epithelium, AAH, a n d well-differentiated adenocarcinoma. T h e r e was no a p p a r e n t difference in total acidic a n d sulfated acidic mucin expression between AAH (63% of cases) a n d a d e n o c a r c i n o m a (60% of cases), but these two lesions h a d greater expression than benign glands (0% o f cases) (Figs 1 a n d 2). T h e frequency of nonsulfated

acidic m u c i n was similar to that of total acidic m u c i n in AAH a n d cancer. T h e n u m b e r of positive glands in benign epithelium, AAH, a n d cancer is listed in Table 1. T h e n u m b e r o f glands with neutral mucin expression was similar between benign glands (mean, 43%), AAH (mean, 52%), and a d e n o c a r c i n o m a (mean, 41%). Cancer was m o r e likely to express total acidic m u c i n (30% of glands) than AAH (11% o f glands). Approximately the same n u m b e r of glands of AAH (12% of glands) and cancer (8% of glands) contained sulfated acidic mucin. T h e r e was no consistant pattern of mucin secretion. Although intraluminal mucin p r e d o m i n a t e d , benign, AAH, a n d malignant glands h a d foci ofintracytoplasmic mucin.

DISCUSSION We f o u n d that acidic m u c i n expression in atypical a d e n o m a t o u s hyperplasia a n d a d e n o c a r c i n o m a was similar, present in a b o u t 60% o f cases, whereas all be-

FIGURE I . Atypical adenomatous hyperplasia of the prostate. (A) Thiscluster of small glands is present in a mildly cellular sclerotic stroma at the periphery of a nodule of nodular hyperplasia. The nuclei are small and the nucleoli are inconspicuous. (Hematoxylin and eosin; original magnification x200.) (B) Scant granular acidic mucin (dark material) is present in the lumens of occasional glands in this case of AAH; none was present in benign glands. (Hematoxylin and eosin stain; original magnification ×400.)

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PROSTATIC AAH (Goldstein et al)

FIGURE 2. Total acidic mucin expression in AAH. (A) Abundant sulfated and nonsulfated acidic mucin is present within the lumens of most glands. (Original magnification x240.) (B) In another case of AAH the glands show abundant but varying amounts of sulfated and nonsulfated acidic mucin. (Combined alcian blue/PAS + diastase, pH 2.7; original magnification x200.)

nign glands were negative. These findings underscore the use of histochemical stains in separating AAH and cancer from benign prostatic epithelium. Also, they suggest that AAH is m o r e closely linked to cancer than to benign epithelium, although the importance of mucin production is uncertain. Acidic mucin expression has been advocated by some as an adjunctive diagnostic test to distinguish benign prostatic glands from adenocarcinoma caused by the production of neutral mucin, acidic mucin, or both by cancer. 24-33'3c~39Others have questioned the diagnostic use of m u c i n s t a i n i n g , 4'0'21'24'35 noting that mucin expression in lesions like AAH has not been studied extensively and that benign glands rarely secrete acidic mucin. 2 4 '26.28 ' '3 4 '3 8 O t h e r lesions also secrete acidic mucin, including mucinous metaplasia, 34 prostatic intraepithelial neoplasia, 35'4° sclerosing adenosis, 41'4z and basal cell hyperplasia (Table 2).43 Our findings indicate that acidic mucin expression in the prostate cannot separate AAH and low grade adenocarcinoma but is useful in distinguishing these lesions from benign glands in the

TABLE 2.

Acidic M u c i n Expression in the Normal a n d Neoplastic Prostate Lesion

Benign epithelium* Basal cell hyperplasiat Mucinous metaplasia + Sclerosing adenosis§ Atypical adenomatous hyperplasia (AAH)* High grade prostatic intraepithelial hyperplasia IJ Well-differentiated adenocarcinoma* * Data 1- Data Data § Data JI Data

from from from from from

No of Positive Cases (%) 0/24 3/3 12/12 10/13 15/24 15/37 3/5

(0) (100) (100) (77) (63) (41) (60)

current study. Grignon et al. 4~ Grignon et al. ~4 Grignon et al and Jones et al. 41'4~ Humphrey 3~ and Sentinelli. 4°

889

majority of cases. O t h e r studies, such as immunohistochemical staining with high molecular weight keratin 34-BE12, specific for the basal cell epithelial layer, are probably more useful. 6'44'45 T h e r e is limited e x p e r i e n c e with m u c i n secretion in AAH. O n e study f o u n d that 54% o f 28 cases o f AAH s e c r e t e d acidic mucin21; these investigators c o n c l u d e d that the practicality o f acidic m u c i n staining in the diagnosis o f a d e n o c a r c i n o m a was limited. T h r e e o f n i n e o t h e r r e p o r t e d cases o f AAH prod u c e d acidic mucin. 28'~s The relationship between AAH and adenocarcin o m a is controversial. Some investigators believe that AAH is benign and that its uniqueness lies in the difficulty in distinguishing it from adenocarcinoma; evidence for a relationship between the two is lacking other than morphological similarities, u'2~'2~ Others have suggested the existence of a relationship, either directly or as an e p i p h e n o m e n o n , v~'a°'12,14,17,46These divergent opinions are probably caused by the lack of well defined histological criteria for AAH, which have only recently emerged. 7 We believe the equivalent expression of acidic mucin in AAH and adenocarcinoma provides biochemical support for a relationship between AAH and well-differentiated adenocarcinoma. A similar relationship exists between high grade PIN and peripheral zone adenocarcinoma, both of which secrete acidic mucin. 35'4° O t h e r investigators have reached a different conclusion based on similar results, and have suggested that acidic mucin expression in AAH was caused by gland size and proliferation rather than evidence of a relationship or reflecting a preneoplastic condition, although no supportive evidence was provided. 21 In addition to histological similarities, other findings suggest a relationship between AAH and adenocarcinoma. Atypical adenomatous hyperplasia is characterized by fragmentation and discontinuity of the basal cell layer, similar to the partial or nearly complete loss

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observed in high grade PIN when it merges with invasive adenocarcinoma. ~'47Expression of blood group isoantigens in AAH is intermediate between benign glands (high levels) and cancer (low levels).4s Peanut agglutinin receptors were present in 53% of cases of welldifferentiated adenocarcinoma and 50% of cases of AAH but absent in benign tissue according to lectin binding studies by Chastonay et al. 4s In support of a relationship Helpap ~° found increased proliferative activity in AAH and carcinoma, unlike simple epithelial hyperplasia, and noted that increased proliferation was present in atypical mucosal lesions in the vicinity of carcinoma in the bladder, stomach, and large bowel. Atypical adenomatous hyperplasia is more comm o n in prostate containing carcinoma than in the benign prostate, ~'11"1vand AAH may be related to transition zone rather than peripheral zone adenocarcin o m a J Transition zone adenocarcinoma comprises approximately 25% of prostatic cancers and is biologically and morphologically distinct from the more c o m m o n peripheral zone adenocarcinoma. 49 It is usually not associated with PIN and has a more favorable prognosis than peripheral zone cancer. Transition zone cancer is also usually well-differentiated, with a tendency to form long tubules and large glands. 4952 Thirty years ago McNeal identified AAH in intimate association with the "alveolar-medullary" pattern of adenocarcinoma and suggested that AAH was a precursor lesion of malignancy, s Intraluminal crystalloids are found in 10% to 62% of low grade cancers 37 '53-55 and are also present in AAH. ~s'46'53"56'~7Gardner identified crystalloids in all five cases of AAH from 51 prostatectomies from 19- to 29year-old patients, including three patients with AAH associated with low grade cancer. 46 Holmes 5~wondered if these atypical crystal-containing glands represented "minimal deviation" carcinoma or a precursor lesion. Similarly, Jensen et a154 questioned whether crystalloids were a feature of "atypicality" or a manifestation of early malignancy. The cumulative data indicate that AAH and adenocarcinoma share the ability to produce crystaUoids, unlike most benign glands. Not all studies have supported a relationship between AAH and adenocarcinoma. The carbohydrate Dgalactose-N-acetyl-D-galactosamine is expressed more frequently in colon carcinoma than benign mucosa. Using a simplified enzymatic reaction for this carbohydrate moiety, Shamsuddin et al2~ identified staining in 95% of cases of prostatic adenocarcinoma but not in AAH or benign prostatic glands. However, they did not define the criteria used to identify AAH and did not use keratin 34-BE12 staining to confirm their histological impression. Our results indicate that there is a similar level of acidic mucin expression in AAH and adenocarcinoma. Identification of acidic mucin should not be used as an adjunctive study in separating these two lesions but may be of value in separating them from benign glands. These findings provide additional support for a close relationship between AAH and well-differentiated adenocarcinoma, but follow-up studies are needed to deter-

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mine the true biological potential and clinical difference, if any, between these lesions.

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