- Email: [email protected]
Adenosis (Atypical Adenomatous Hyperplasia): Histopathology and Relationship to Carcinoma
Path. Res. Pract. 191, 888 - 898 (1995)
Adenosis (Atypical Adenomatous Hyperplasia): Histopathology and Relationship to Carcinoma J. I. Epstein The Johns Hopkins Medical Institutions, Department of Pathology, Baltimore, Maryland, U.S.A.
SUMMARY Adenosis is a specific histologic entity which is most frequently seen in transurethral resection of the prostate, although increasingly identified on needle biopsy. The distinction of adenosis from low-grade adenocarcinoma is based on a constellation of histologic features, rather than on anyone specific feature (ie. nucleoli). Although mimicking low grade adenocarcinoma, adenosis has not been shown to be related to adenocarcinoma.
Terminology One of the most common lesions that may be confused with carcinoma is adenosis. Other terms for adenosis include "atypical adenomatous hyperplasia"2, "atypical adenosis" and "small acinar atypical hyperplasia"18. The preferred terminology for this lesion is controversial. Recently a group of urological pathologists came out in support of the term "atypical adenomatous hyperplasia (AAH)." Support for this term was that: 1) it is in wide use; 2) its name accurately describes its morphology; and 3) this term would be more appropriate if this lesion is found to be a precursor of prostate cancer3. This author prefers the term "adenosis"lo. Prefacing "adenomatous hyperplasia" with "atypical" has adverse consequences both in terms of practical patient management and in our theoretical framework of this entity. As outlined below, there is very little data in support of a relation between adenosis and carcinoma. By designating these lesions as "atypical," many patients will be subjected to unnecessary repeat biopsies. Conceptually, as has happened in the past, use of the term "atypical adenomatous hyperplasia" will result in this entity being considered with PIN as precursors to carcinoma of the prostate. Whereas there is strong evi0344-0338/95/0191-0888$3.50/0
dence that PIN is a precursor to some prostate cancers, this evidence is lacking in adenosis. A majority of the participants favored the term AAH, although there was a wide range in how strong pathologists felt about the issue. Some pathologists argued for uniformity in terminology, with AAH as the only possible term for this lesion. Others felt that the terminology was not as critical as our definition and understanding of the lesion. A minority of pathologists expressed strong reservations concerning the term AAH. A difference was noted in the response of European urologists to the word "atypical" as compared to American urologists. A report with the word "atypical" will usually cause greater concern in the United States and often lead to repeat exams and biopsies. In Europe this does not appear to be the case. Also, in Europe at the current time, the distinction between this lesion and low grade adenocarcinoma was not thought to be as critical, since many patients with limited low grade carcinoma are followed there expectantly. In contrast, a single focus of low grade carcinoma on needle biopsy is treated definitively in the United States, as may be the case when limited low grade carcinoma is found on transurethral resection of the prostate (TURP) in a relatively young man. Throughout this © 1995 by Gustav Fischer Verlag, Stuttgart
Fig. 1. Well circumscribed nodule of adenosis. Note intermingled among small glands suspicious for carcinoma, larger elongated glands with occasional branching more typical of benign glands (reprinted with permission from Epstein JI, Prostate Biopsy Interpretation. Raven Press, New York, NY, 1989). - Fig. 2. Well circumscribed nodule of adenosis with scattered large benign appearing glands in and amongst similar looking smaller glands (reprinted with permission from Epstein JI, Prostate Biopsy Interpretation. Raven Press, New York, NY,1989). - Fig. 3. Low grade adenocarcinoma with haphazard infiltration in stroma. Note glands are separated by bundles of smooth muscle indicative of infiltration. - Fig. 4. Infiltrative pattern of low grade adenocarcinoma. Note glands do not merge in with surrounding benign appearing glands.
890 . J. I. Epstein
manuscript this author will use the term "adenosis" since that is his preference, with the recognition that AAH was the recommended term of the pathologists at the meeting. Incidence In our institution, 1.6% of benign TURs and 0.8% of all needle biopsies contain adenosis 11 ,12. Adenosis describes a benign glandular lesion with typical histologic features that may be confused with carcinoma. In general, adenosis consists of a crowded focus of small glands which mimics low-grade adenocarcinoma 2, 11, 12. In the spectrum of architectural atypia which ranges from obviously benign glands which are somewhat crowded, to areas which are difficult to distinguish from carcinoma, the diagnosis of adenosis should be restricted to cases which are sufficiently atypical in their growth pattern when one has to consider seriously the diagnosis of low-grade cancer. It is characteristically found in the transition zone (periurethral region) of the prostate, frequently multi-focal, and most often an incidental finding in TURs performed for urinary obstruction.
Diagnosis on TURP The distinction of adenosis from low-grade adenocarcinoma is based on architectural and cytologic features (Table 1). In order to minimize misdiagnoses, the constellation of histologic features seen in a lesion should outweigh the significance of anyone diagnostic feature. At scanning magnification, adenosis is characterized by a lobular proliferation of small glands (Figures 1&2). In contrast, low grade carcinomas have a haphazard, irregular, infiltrative growth pattern (Figures 3&4). Despite the overall lobular pattern seen in adenosis, in 19% of the cases there may be minimal infiltration into the surrounding stroma (Figure 5)11. Within a nodule of adenosis there are elongated glands with papillary infolding and branching lumina typical of more benign glands, yet in their cytoplasmic features they look similar to the adjacent small glands suspicious for carcinoma (Figures 6&7). Another common feature seen is the budding off of glands of adenosis from obviously benign glands (Figure 8). With carcinoma there is an abrupt interface between the small neoplastic glands and the adjacent larger architecturally benign surrounding glands.
Table 1. Diagnostic criteria for adenosis Adenosis
Low grade carcinoma
Features seen at low and intermediate magnification Lobular growth"
May be infiltrative/haphazard
Small crowded glands admixed with larger glands
May be pure population of small crowded glands
Features seen at high magnification Huge (> 3 micron) nucleoli absent*
Occasionally huge nucleoli present
Small glands share cytoplasmic and nuclear features with admixed larger benign glands*
Small glands differ from surrounding benign glands in cytoplasmic and/or nuclear features
Pale-clear cytoplasm
May have amphophilic cytoplasm
Blue-tinged mucinous secretions rare
Blue-tinged mucinous secretions common
Corpora amylacea common
Corpora amyl ace a rare
Occasional glands with basal cells
Basal cells absent
Basal cell-specific anti-keratin * antibodies label basal cells in some small glands
Small glands are not immunoreactive with basal cell-specific anti-keratin antibodies
* Most important criteria, reprinted with permission from Ref. 12.
Fig. 5. Adenosis with minimal infiltration at its perimeter. Case was verified as adenosis with stains for high molecular weight ~ cytokeratin. - Fig. 6. Adenosis. Note gland with small papillary projections typical of a benign gland with the same nuclear and cytoplasmic features of surrounding small glands (reprinted with permission from Epstein JI, Prostate Biopsy Interpretation. Raven Press, New York, NY, 1989). - Fig. 7. Adenosis with benign appearing larger glands with branching and papillary infolding admixed with small crowded pale staining glands. Note the similar nuclear and cytoplasmic features of the more recognizable benign glands and the crowded small glands (reprinted with permission from Reference 11). - Fig. 8. Adenosis showing budding off of the glands from peripherally situated benign appearing glands (reprinted with permission from Epstein JI Prostate Biopsy Interpretation. Raven Press, New York, NY 1989).
892 .
J. I. Epstein
At higher power, adenosis is typically composed of small glands with pale to clear cytoplasm, as opposed to some carcinomas which have more amphophilic cytoplasm(Figure 9). In order for this feature to be diagnostically useful, the cytoplasm of benign prostate glands should appear pale or clear on routinely stained slides. One must not jump to a diagnosis of carcinoma based on what appears to be either a few individual cells or poorly formed glands within a nodule that is otherwise typical of adenosis (Figure 10). Occasional single cells or poorly formed glands are not uncommon in a nodule of adenosis and probably represent tangential sections of small glands (Table 1). Usually, adenosis has been described as having totally bland appearing nuclei without nucleoli. This is generally valid; most (60%) lesions contain no or at most rare prominent nucleoli. In the other 40%, fairly prominent (> 1.6 microns) nucleoli are present, which should not lead to the diagnosis of carcinoma (Figure 11)14. In another study, 18% contained nucleoli larger than 1 micron 2 • Only huge nucleoli (> 3 um) are incompatible with a diagnosis of adenosis (Figure 12). In contrast, the majority (70%) of foci of low grade adenocarcinoma have occasional or frequent large nucleoli. The remaining low grade cancers show no prominent or rare prominent nucleoli. These findings emphasize that, although nucleoli are generally helpful in differentiating adenosis from adenocarcinoma, there is overlap between the two entities. In this differential diagnosis, the presence of prominent nucleoli should not necessarily be given any more diagnostic weight than any of the other light microscopic features. In most cases, a constellation of features must be evaluated to differentiate the two entities. The luminal contents may also be useful in this differential diagnosis. Corpora amylacea are commonly seen in adenosis, and are rare in carcinoma. Only 2 % of the cases of adenosis contain blue intraluminal secretions visible on hematoxylin and eosin-stained sections, a feature common in low-grade carcinomas 11. It is not helpful to perform special stains for mucin. Despite earlier studies' claims that acid mucin was diagnostic of carcinoma, a later work found that 54% of foci of adenosis contained acid mucin secretions 8 • Crystalloids are another intraluminal structure that has been touted as distinguishing adenosis from carcinoma. However, 18% -39% of foci of adenosis contain crystalloids, sometimes in great number (Figures 10& 13 )2, 11, 12. Thus, crystalloids should not be used to differentiate adenosis and carcinoma (Table 2). Basal cells are the one feature seen in adenosis that is never seen in carcinoma. Although basal cells may be difficult to identify within many of the glands, a flattened basal cell layer can be seen in at least some of
Table 2. Nondiagnostic features in adenosis and carcinoma Features Shared in Adenosis and Cancer Crowded (back-to-back glands) Intraluminal crystalloids Medium-sized « 3 microns) nucleoli Scattered poorly formed glands and single cells Minimal infiltration at periphery of nodule Reprinted with permission from Ref. 12.
the glands. As long as the glands with a basal cell layer are otherwise identical to the glands where a basal cell layer can not be identified, then the entire lesion is benign. It is important to distinguish basal cells from adjacent fibroblasts. While fibroblasts have elongated pointed hyperchromatic nuclei, basal cells which are recognizable in routine sections have a more cigarshaped ovoid contour with chromatin similar to that of the overlying secretory cells (Figure 13). In foci of glandular crowding where all of the features are typical of adenosis and there is no cytologic atypia, one can make the diagnosis without immunohistochemical stains even if basal cells are not visible on routine sections. In cases in which the architectural pattern favors adenosis, yet there are large nucleoli, the diagnosis can be clarified using immunohistochemistry for basal cells. The use of a basal cell specific antibody to high molecular weight keratin is helpful since some glands will show a thin rim of keratin immunoreactivity underneath the cuboidal or columnar secretory cells ll , 12,13 (Figure 14). Corresponding to the discontinuous patchy distribution of basal cells seen in routine sections, as few as 10% of the glands in a nodule of adenosis may be labeled with antibodies to high molecular keratin, although usually more than half of the glands will show some staining. If some glands suspicious for adenosis lack high molecular weight cytokeratin immunoreactivity, yet are otherwise indistinguishable from adjacent glands which demonstrate basal cell keratin immunoreactivity, the absence of a basal cell layer in some glands should not be used to diagnose the lesion as carcinoma. Some of the variability in basal cell immunoreactivity within adenosis and other lesions may be caused by tissue processing since more uniform immunoreactivity has been observed in frozen tissue. Of the more than 300 reported cases of adenocarcinoma of the prostate that have been studied with high molecular weight cytokeratin, only rare positive staining has been noted in one case 4,13 , 15-1 7,20.
Fig. 9. Typical high magnification appearance of adenosis with glands containing cells with pale to clear cytoplasm, relatively ~ benign appearing nuclei and cells suggestive of basal cells. - Fig. 10. Case of adenosis with crystalloids a nd occasional single
cells (arrow). - Fig. 11. Adenosis with nucleoli approximately 1.6 micron in greatest diameter (arrows) (reprinted with permission from reference 14). - Fig. 12. Intermediate grade adenocarcinoma with huge (> 3 micron) nucleoli (reprinted with permission from reference 14).
Adenosis (Atypical Adenomatous Hyperplasia) . 893
894 . ]. I. Epstein
Adenosis often appears to be multifocal. Foci in a few cases are so numerous that, if misdiagnosed as carcinoma, they would be classified as stage Tl b, leading to unwarranted radical therapy. The distinction between adenosis and low grade adenocarcinoma in even a single focus may be critical, since diagnosis of even a single focus of carcinoma on TURP in a relatively young man may lead to aggressive surgery. Diagnosis on Needle Biopsy Adenosis occurs most frequently within the central region of the gland and is often seen on TURP specimens where one can appreciate its typical low magnification architectural pattern, as well as evaluate a substantial number of glands for the presence of a basal cell layer. Recently, the number of cases of adenosis seen on needle biopsy has also increased 12 • These are more likely to be misdiagnosed as carcinoma, since it is more difficult to appreciate their architectural pattern. At low magnification, adenosis on needle biopsy consisted of a relatively well localized nodule of closely packed glands with pale to clear cytoplasm. In only 7% of the foci was the entire lobular lesion visualized on needle biopsy. In 45% of the foci, one could appreciate one edge of the nodule which was circumscribed, yet the other side was not visible since the lesion was bisected by one edge of the needle biopsy6. The remaining 48% of the foci were transected in the middle of the nodule of adenosis such that the lesion extended to both edges of the needle biopsy 6. Although in these cases assessment of circumscription was difficult, in all but 3 cases the foci of adenosis occupied a small portion of the core length. In three cases, adenosis occupied > 3 mm of the core length. Intermediate magnification of adenosis showed larger benign appearing glands with papillary infolding and luminal undulations merging in with small crowded glands. At high magnification, the small glands suspicious for carcinoma shared nuclear and cytoplasmic features with the more recognizable benign glands (Figure 17). The cytoplasm of the glands was pale to clear. While most foci of adenosis consisted of well-formed glands, 11 % of the cases revealed occasional poorly formed glands and/or individual cells which probably represent tangential sections of the small glands of adenosis. In the majority of cases, nuclei are benign appearing without prominent nucleoli. In 73 % of the cases, basal cells were focally identifiable on hematoxylin and eosin (H&E) stained sections. When considering the diagnosis of low grade carcinoma on needle biopsy, one should always question whether a lesion may be adenosis 12 • When the small crowded glands have identical nuclear and cytoplasmic features as surrounding more recognizable glands, then the focus may be adenosis. If one is thinking of diagnosing a nodule of adenosis as cancer, it would be difficult to determine where the "cancer" ends and the benign glands begin, since the small glands of adenosis
merge in with the surrounding more recognizable benign glands. In contrast, glands of carcinoma stand out from surrounding benign glands by their darker cytoplasm, enlarged nuclei, prominent nucleoli and intraluminal contents. Figure 18 shows a nodule of low grade cancer which is homogeneous and does not merge in with adjacent benign glands. The presence of non-branching glands with straight luminal borders is also diagnostic of low-grade cancer (Figure 19). A study of 77 foci of adenosis in needle biopsies found that mitotic figures and blue mucin were uncommon 12 . In needle biopsy specimens, occasional single cells and a minimally infiltrative pattern may be seen in about 12 % of the lesions, crystalloids in 24% of the cases, and some nucleoli in 13% of the foci. Basal cell specific antibodies must be interpreted with caution on needle biopsies. Because basal cell staining may be patchy in adenosis, negative staining in a small focus of glands is not necessarily indicative of malignancy. However, if some of the glands within a crowded glandular focus on needle biopsy demonstrate a basal cell layer, then adenosis can be diagnosed. Because of the difficulty in diagnosing adenosis on needle biopsy, it is useful to verify the diagnosis with high molecular weight cytokeratin antibodies.
Relation of Adenosis to Cancer Although adenosis mimics carcinoma, there is no conclusive evidence suggesting that these patients have an increased risk of harboring or developing adenocarcinoma of the prostate. In our series of adenosis, 14 % of the TUR specimens examined contained incidental foci of adenocarcinoma of the prostate 11 • This is similar to the reported frequency of incidental adenocarcinomas found in TURs performed for clinically benign disease. Prior reports of transitions between adenosis and carcinoma were not verified with the use of basal cell specific antibodies, and may have been adenosis with foci of individual cells, minimal infiltration, or visible nucleoli. Another argument that has been raised to suggest that adenosis is a precursor to prostate cancer is that the two entities share certain morphologic features. Several studies have shown that adenosis may contain acid mucin, crystalloids, nucleoli and have a patchy basal cell layer. Rather than proving a relation between adenosis and carcinoma, these Jindings demonstrate that anyone of these features, by itself, is not specific for carcinoma. For example, acid mucin may be seen in atrophy8, a patchy basal cell layer in clear cell cribriform hyperplasia 1 and nucleoli in basal cell hyperplasia 9• None of these lesions is a precursor to prostate cancer. The interpretation of these features must be made in the context of the totality of a lesion's architectural and cytologic features. A recent study from M.D. Anderson Cancer Center supports the lack of association between adenosis and
•
~':
·r :
Fig. 13. Adenosis with multiple crystalloids (open arrows). Note luminal ruffling in several of the glands which favors adenosis. Also note the presence of a well defined basal cell layer surrounding some of the glands (arrow). Basal cell stains were positive in this case. - Fig. 14. Adenosis labeled with antibodies to high molecular weight cytokeratin showing numerous cytokeratin positive basal cells. - Fig. 15. Adenosis on needle biopsy. The edge of the lesion which has not been transected by the biopsy appears lobular. - Fig. 16. Classic example of adenosis on needle biopsy with benign glands with papillary infolding and branching merging in with small crowded glands with pale-clear cytoplasm. Note corpora amylacea.
'" ,
~ ••:,~ 4 '.
,
....:.. f \,'
'<.....
.
';:\.. I' \to ~ .' •
'.
:".. ; :
r. ~
..
I I , JI
.,
I •
., '
Fig. 17. High magnification of adenosis showing benign appearing glands with papillary infolding and luminal undulations. Admixed crowded glands share nuclear and cytoplasmic features with more recognizable benign glands. - Fig. 18, 20. Low grade adenocarcinoma on needle biopsy. The nodule of adenocarcinoma consists of a uniform population of small glands without branching or papillary infolding (i.e. benign features). This nodule is distinct and does not merge in with adjacent benign larger glands with pale-clear cytoplasm. Note corpora amylacea. - Fig. 19. Low grade adenocarcinoma composed of uniform glands with straight luminal borders. Numerous crystalloids are present.
Adenosis (Atypical Adenomatous Hyperplasia) . 897
nant lesion. In reporting adenosis, it may be helpful to add the following note: "Adenosis, although mimicking adenocarcinoma of the prostate, has not been shown to be associated with an increased risk of carcinoma."
References
Fig. 21. High magnification of adenosis showing benign appearing glands with papillary infolding and luminal undulations. Admixed small crowded glands share nuclear and cytoplasmic features with more recognizable benign glands.
cancer19. They studied 60 prostates from men who underwent cystoprostatectomy for bladder cancer. Fortyone prostates were found to have incidental prostate cancer and 12 were found to have adenosis, which they termed "atypical small glandular proliferations." They subcategorized cases of adenosis into cases with and without architectural and/or cytologic atypia. The overall prevalence of adenosis in prostates with and without carcinoma was not significantly different. The distribution of adenosis with and without atypical features also did not differ significantly between cases with and without carcinoma. There was no topographic association between either form of adenosis and carcinoma. Those studies suggesting a higher risk of carcinoma in men with adenosis have defined it differently, including many examples of what most authorities would call carcinoma s,6. Whether cases of adenosis with more prominent nucleoli differ from more ordinary cases in their association with adenocarcinoma remains unknown. Until long-term follow-up studies are performed to assess the risk of developing adenocarcinoma, adenosis should not be classified as a pre-malig-
1 Ayala AG, Srigley]R, Ro ]Y, Abdul-Karin FW, Johnson DE (1986) Clear cell cribriforming hyperplasia of prostate: Report of ten cases. Am ] Surg Pathol 10: 665 - 71 2 Bostwick DG, Srigley], Grignon D et al. (1993) Atypical adenomatous hyperplasia of the prostate: morphologic criteria for its distinction from well-differentiated carcinoma. Hum Pathol24: 819-832 3 Bostwick DG, Algaba F, Amin MB, Ayala A, Eble ], Goldstein N, Helpap B, Humphrey P, Grignon D, Jones EC, McNeal ], Montironi R, Qian ], Ro ], Srigley ], Tetu B, Troncoso P, True L, Wheeler T, Young RH (1994) Consensus statement on terminology: Recommendation to use atypical adenomatous hyperplasia in place of adenosis of the prostate. Am] Surg Pathol18: 1069-1070 4 Brawer MK, Peehl DM, Stamey TA, Bostwick DG (1985) Keratin immunoreactivity in the benign and neoplastic human prostate. Cancer Research 45: 3663-7 5 Brawn PN (1982) Adenosis of the prostate: A dysplastic lesion that can be confused with prostate adenocarcinoma. Cancer 49: 826 - 833 6 Brawn PN (1983) Interpretation of prostate biopsies. New York: Raven Press, 48-81 7 Epstein ]1 (1989) Disorders of the prostate gland. In: Sternberg SS, ed. Diagnosis in Surgical Pathology. New York: Raven Press, 1293-1432 8 Epstein ]1, Fynheer] (1992a) Acidic mucin in the prostate: can it differentiate adenosis from adenocarcinoma? Human Pathol 23: 1321-1325 9 Epstein ]1, Armas OA (1992b) Atypical basal cell hyperplasia of the prostate. Am] Surg Pat hoi 16: 1205-1214 10 Epstein]1 (1994) Adenosis vs. atypical adenomatous hyperplasia of the prostate. Am] Surg Pathol18: 1070-1071 11 Gaudin PB, Epstein ]1 (1994) Adenosis of the Prostate: Histologic features in transurethral resection specimens. Am] Surg Pathol18: 863-870 12 Gaudin PB, Epstein ]1 1995 Adenosis of the Prostate: Histologic features in needle biopsy specimens. Am J Surg Pathol19: 737-747 13 Hedrick L, Epstein ]1 (1989) Use of keratin 903 as an adjunct in the diagnosis of prostate carcinoma. Am ] Surg Pathol13: 389-96 14 Kramer CE, Epstein ]1 (1993) Nucleoli in low-grade prostate adenocarcinoma and Hum Pathol 24: 618-623 15 Nagle RB, Ahmann FR, McDaniel KM, Paquin ML, Clark VA, Celniker A (1987) Cytokeratin Characterization of Human Prostatic Carcinoma and Its Derived Cell Lines. Cancer Research 47: 281-286 16 Okada H, Tsubura A, Okamura A, Senzaki H, Naka Y, Komatz Y, Morii S (1992) Keratin profiles in normal/hyperplastic prostates and prostate carcinoma. Virchows Archiv A, Pathological Anatomy & Histopathology 421: 157-61 17 O'Malley FP, Grignon D], Shum DT (1990) Usefulness of immunoperoxidase staining with high-molecular-weight cytokeratin in the differential diagnosis of small-acinar lesions of the prostate gland. Virchows Archiv - A, Pathological Anatomy & Histopathology 417: 191-6
898 .
J.
I. Epstein
18 Petersen RO (1992) Urologic Pathology. Philadelphia: J.B. Lippincott 19 Shah lA, Schlageter MO, Stinnett P, Lechago J (1991) Cytokeratin immunohistochemistry as a diagnostic tool for distinguishing malignant from benign epithelial lesions of the prostate. Mod Pathol 4: 220-4
20 Troncoso P, Ayala AG ( 1994) Atypical small gland proliferations of the transition zone in cystoprostatectomy specimens. Mod Pathol 7: 85A 21 Wojno KJ, Epstein Jl (1995) The utility of basal cell specific anti-cytokeratin antibody (34 beta E12) in the diagnosis of prostate cancer: a review of 228 cases. Am J Surg Pathol
Received December 20, 1994 . Accepted in revised form June 10, 1995
Key words: Adenosis - Atypical adenomatous hyperplasia - Adenocarcinoma of the prostate - High molecular weight cytokeratin Jonathan I. Epstein, M.D., Johns Hopkins Hospital, Department of Pathology, 600 N. Wolfe Street, Baltimore, MD 21287, U.S.A.
Adenosis (Atypical Adenomatous Hyperplasia): Histopathology and Relationship to Carcinoma J. I. Epstein The Johns Hopkins Medical Institutions, Department of Pathology, Baltimore, Maryland, U.S.A.
SUMMARY Adenosis is a specific histologic entity which is most frequently seen in transurethral resection of the prostate, although increasingly identified on needle biopsy. The distinction of adenosis from low-grade adenocarcinoma is based on a constellation of histologic features, rather than on anyone specific feature (ie. nucleoli). Although mimicking low grade adenocarcinoma, adenosis has not been shown to be related to adenocarcinoma.
Terminology One of the most common lesions that may be confused with carcinoma is adenosis. Other terms for adenosis include "atypical adenomatous hyperplasia"2, "atypical adenosis" and "small acinar atypical hyperplasia"18. The preferred terminology for this lesion is controversial. Recently a group of urological pathologists came out in support of the term "atypical adenomatous hyperplasia (AAH)." Support for this term was that: 1) it is in wide use; 2) its name accurately describes its morphology; and 3) this term would be more appropriate if this lesion is found to be a precursor of prostate cancer3. This author prefers the term "adenosis"lo. Prefacing "adenomatous hyperplasia" with "atypical" has adverse consequences both in terms of practical patient management and in our theoretical framework of this entity. As outlined below, there is very little data in support of a relation between adenosis and carcinoma. By designating these lesions as "atypical," many patients will be subjected to unnecessary repeat biopsies. Conceptually, as has happened in the past, use of the term "atypical adenomatous hyperplasia" will result in this entity being considered with PIN as precursors to carcinoma of the prostate. Whereas there is strong evi0344-0338/95/0191-0888$3.50/0
dence that PIN is a precursor to some prostate cancers, this evidence is lacking in adenosis. A majority of the participants favored the term AAH, although there was a wide range in how strong pathologists felt about the issue. Some pathologists argued for uniformity in terminology, with AAH as the only possible term for this lesion. Others felt that the terminology was not as critical as our definition and understanding of the lesion. A minority of pathologists expressed strong reservations concerning the term AAH. A difference was noted in the response of European urologists to the word "atypical" as compared to American urologists. A report with the word "atypical" will usually cause greater concern in the United States and often lead to repeat exams and biopsies. In Europe this does not appear to be the case. Also, in Europe at the current time, the distinction between this lesion and low grade adenocarcinoma was not thought to be as critical, since many patients with limited low grade carcinoma are followed there expectantly. In contrast, a single focus of low grade carcinoma on needle biopsy is treated definitively in the United States, as may be the case when limited low grade carcinoma is found on transurethral resection of the prostate (TURP) in a relatively young man. Throughout this © 1995 by Gustav Fischer Verlag, Stuttgart
Fig. 1. Well circumscribed nodule of adenosis. Note intermingled among small glands suspicious for carcinoma, larger elongated glands with occasional branching more typical of benign glands (reprinted with permission from Epstein JI, Prostate Biopsy Interpretation. Raven Press, New York, NY, 1989). - Fig. 2. Well circumscribed nodule of adenosis with scattered large benign appearing glands in and amongst similar looking smaller glands (reprinted with permission from Epstein JI, Prostate Biopsy Interpretation. Raven Press, New York, NY,1989). - Fig. 3. Low grade adenocarcinoma with haphazard infiltration in stroma. Note glands are separated by bundles of smooth muscle indicative of infiltration. - Fig. 4. Infiltrative pattern of low grade adenocarcinoma. Note glands do not merge in with surrounding benign appearing glands.
890 . J. I. Epstein
manuscript this author will use the term "adenosis" since that is his preference, with the recognition that AAH was the recommended term of the pathologists at the meeting. Incidence In our institution, 1.6% of benign TURs and 0.8% of all needle biopsies contain adenosis 11 ,12. Adenosis describes a benign glandular lesion with typical histologic features that may be confused with carcinoma. In general, adenosis consists of a crowded focus of small glands which mimics low-grade adenocarcinoma 2, 11, 12. In the spectrum of architectural atypia which ranges from obviously benign glands which are somewhat crowded, to areas which are difficult to distinguish from carcinoma, the diagnosis of adenosis should be restricted to cases which are sufficiently atypical in their growth pattern when one has to consider seriously the diagnosis of low-grade cancer. It is characteristically found in the transition zone (periurethral region) of the prostate, frequently multi-focal, and most often an incidental finding in TURs performed for urinary obstruction.
Diagnosis on TURP The distinction of adenosis from low-grade adenocarcinoma is based on architectural and cytologic features (Table 1). In order to minimize misdiagnoses, the constellation of histologic features seen in a lesion should outweigh the significance of anyone diagnostic feature. At scanning magnification, adenosis is characterized by a lobular proliferation of small glands (Figures 1&2). In contrast, low grade carcinomas have a haphazard, irregular, infiltrative growth pattern (Figures 3&4). Despite the overall lobular pattern seen in adenosis, in 19% of the cases there may be minimal infiltration into the surrounding stroma (Figure 5)11. Within a nodule of adenosis there are elongated glands with papillary infolding and branching lumina typical of more benign glands, yet in their cytoplasmic features they look similar to the adjacent small glands suspicious for carcinoma (Figures 6&7). Another common feature seen is the budding off of glands of adenosis from obviously benign glands (Figure 8). With carcinoma there is an abrupt interface between the small neoplastic glands and the adjacent larger architecturally benign surrounding glands.
Table 1. Diagnostic criteria for adenosis Adenosis
Low grade carcinoma
Features seen at low and intermediate magnification Lobular growth"
May be infiltrative/haphazard
Small crowded glands admixed with larger glands
May be pure population of small crowded glands
Features seen at high magnification Huge (> 3 micron) nucleoli absent*
Occasionally huge nucleoli present
Small glands share cytoplasmic and nuclear features with admixed larger benign glands*
Small glands differ from surrounding benign glands in cytoplasmic and/or nuclear features
Pale-clear cytoplasm
May have amphophilic cytoplasm
Blue-tinged mucinous secretions rare
Blue-tinged mucinous secretions common
Corpora amylacea common
Corpora amyl ace a rare
Occasional glands with basal cells
Basal cells absent
Basal cell-specific anti-keratin * antibodies label basal cells in some small glands
Small glands are not immunoreactive with basal cell-specific anti-keratin antibodies
* Most important criteria, reprinted with permission from Ref. 12.
Fig. 5. Adenosis with minimal infiltration at its perimeter. Case was verified as adenosis with stains for high molecular weight ~ cytokeratin. - Fig. 6. Adenosis. Note gland with small papillary projections typical of a benign gland with the same nuclear and cytoplasmic features of surrounding small glands (reprinted with permission from Epstein JI, Prostate Biopsy Interpretation. Raven Press, New York, NY, 1989). - Fig. 7. Adenosis with benign appearing larger glands with branching and papillary infolding admixed with small crowded pale staining glands. Note the similar nuclear and cytoplasmic features of the more recognizable benign glands and the crowded small glands (reprinted with permission from Reference 11). - Fig. 8. Adenosis showing budding off of the glands from peripherally situated benign appearing glands (reprinted with permission from Epstein JI Prostate Biopsy Interpretation. Raven Press, New York, NY 1989).
892 .
J. I. Epstein
At higher power, adenosis is typically composed of small glands with pale to clear cytoplasm, as opposed to some carcinomas which have more amphophilic cytoplasm(Figure 9). In order for this feature to be diagnostically useful, the cytoplasm of benign prostate glands should appear pale or clear on routinely stained slides. One must not jump to a diagnosis of carcinoma based on what appears to be either a few individual cells or poorly formed glands within a nodule that is otherwise typical of adenosis (Figure 10). Occasional single cells or poorly formed glands are not uncommon in a nodule of adenosis and probably represent tangential sections of small glands (Table 1). Usually, adenosis has been described as having totally bland appearing nuclei without nucleoli. This is generally valid; most (60%) lesions contain no or at most rare prominent nucleoli. In the other 40%, fairly prominent (> 1.6 microns) nucleoli are present, which should not lead to the diagnosis of carcinoma (Figure 11)14. In another study, 18% contained nucleoli larger than 1 micron 2 • Only huge nucleoli (> 3 um) are incompatible with a diagnosis of adenosis (Figure 12). In contrast, the majority (70%) of foci of low grade adenocarcinoma have occasional or frequent large nucleoli. The remaining low grade cancers show no prominent or rare prominent nucleoli. These findings emphasize that, although nucleoli are generally helpful in differentiating adenosis from adenocarcinoma, there is overlap between the two entities. In this differential diagnosis, the presence of prominent nucleoli should not necessarily be given any more diagnostic weight than any of the other light microscopic features. In most cases, a constellation of features must be evaluated to differentiate the two entities. The luminal contents may also be useful in this differential diagnosis. Corpora amylacea are commonly seen in adenosis, and are rare in carcinoma. Only 2 % of the cases of adenosis contain blue intraluminal secretions visible on hematoxylin and eosin-stained sections, a feature common in low-grade carcinomas 11. It is not helpful to perform special stains for mucin. Despite earlier studies' claims that acid mucin was diagnostic of carcinoma, a later work found that 54% of foci of adenosis contained acid mucin secretions 8 • Crystalloids are another intraluminal structure that has been touted as distinguishing adenosis from carcinoma. However, 18% -39% of foci of adenosis contain crystalloids, sometimes in great number (Figures 10& 13 )2, 11, 12. Thus, crystalloids should not be used to differentiate adenosis and carcinoma (Table 2). Basal cells are the one feature seen in adenosis that is never seen in carcinoma. Although basal cells may be difficult to identify within many of the glands, a flattened basal cell layer can be seen in at least some of
Table 2. Nondiagnostic features in adenosis and carcinoma Features Shared in Adenosis and Cancer Crowded (back-to-back glands) Intraluminal crystalloids Medium-sized « 3 microns) nucleoli Scattered poorly formed glands and single cells Minimal infiltration at periphery of nodule Reprinted with permission from Ref. 12.
the glands. As long as the glands with a basal cell layer are otherwise identical to the glands where a basal cell layer can not be identified, then the entire lesion is benign. It is important to distinguish basal cells from adjacent fibroblasts. While fibroblasts have elongated pointed hyperchromatic nuclei, basal cells which are recognizable in routine sections have a more cigarshaped ovoid contour with chromatin similar to that of the overlying secretory cells (Figure 13). In foci of glandular crowding where all of the features are typical of adenosis and there is no cytologic atypia, one can make the diagnosis without immunohistochemical stains even if basal cells are not visible on routine sections. In cases in which the architectural pattern favors adenosis, yet there are large nucleoli, the diagnosis can be clarified using immunohistochemistry for basal cells. The use of a basal cell specific antibody to high molecular weight keratin is helpful since some glands will show a thin rim of keratin immunoreactivity underneath the cuboidal or columnar secretory cells ll , 12,13 (Figure 14). Corresponding to the discontinuous patchy distribution of basal cells seen in routine sections, as few as 10% of the glands in a nodule of adenosis may be labeled with antibodies to high molecular keratin, although usually more than half of the glands will show some staining. If some glands suspicious for adenosis lack high molecular weight cytokeratin immunoreactivity, yet are otherwise indistinguishable from adjacent glands which demonstrate basal cell keratin immunoreactivity, the absence of a basal cell layer in some glands should not be used to diagnose the lesion as carcinoma. Some of the variability in basal cell immunoreactivity within adenosis and other lesions may be caused by tissue processing since more uniform immunoreactivity has been observed in frozen tissue. Of the more than 300 reported cases of adenocarcinoma of the prostate that have been studied with high molecular weight cytokeratin, only rare positive staining has been noted in one case 4,13 , 15-1 7,20.
Fig. 9. Typical high magnification appearance of adenosis with glands containing cells with pale to clear cytoplasm, relatively ~ benign appearing nuclei and cells suggestive of basal cells. - Fig. 10. Case of adenosis with crystalloids a nd occasional single
cells (arrow). - Fig. 11. Adenosis with nucleoli approximately 1.6 micron in greatest diameter (arrows) (reprinted with permission from reference 14). - Fig. 12. Intermediate grade adenocarcinoma with huge (> 3 micron) nucleoli (reprinted with permission from reference 14).
Adenosis (Atypical Adenomatous Hyperplasia) . 893
894 . ]. I. Epstein
Adenosis often appears to be multifocal. Foci in a few cases are so numerous that, if misdiagnosed as carcinoma, they would be classified as stage Tl b, leading to unwarranted radical therapy. The distinction between adenosis and low grade adenocarcinoma in even a single focus may be critical, since diagnosis of even a single focus of carcinoma on TURP in a relatively young man may lead to aggressive surgery. Diagnosis on Needle Biopsy Adenosis occurs most frequently within the central region of the gland and is often seen on TURP specimens where one can appreciate its typical low magnification architectural pattern, as well as evaluate a substantial number of glands for the presence of a basal cell layer. Recently, the number of cases of adenosis seen on needle biopsy has also increased 12 • These are more likely to be misdiagnosed as carcinoma, since it is more difficult to appreciate their architectural pattern. At low magnification, adenosis on needle biopsy consisted of a relatively well localized nodule of closely packed glands with pale to clear cytoplasm. In only 7% of the foci was the entire lobular lesion visualized on needle biopsy. In 45% of the foci, one could appreciate one edge of the nodule which was circumscribed, yet the other side was not visible since the lesion was bisected by one edge of the needle biopsy6. The remaining 48% of the foci were transected in the middle of the nodule of adenosis such that the lesion extended to both edges of the needle biopsy 6. Although in these cases assessment of circumscription was difficult, in all but 3 cases the foci of adenosis occupied a small portion of the core length. In three cases, adenosis occupied > 3 mm of the core length. Intermediate magnification of adenosis showed larger benign appearing glands with papillary infolding and luminal undulations merging in with small crowded glands. At high magnification, the small glands suspicious for carcinoma shared nuclear and cytoplasmic features with the more recognizable benign glands (Figure 17). The cytoplasm of the glands was pale to clear. While most foci of adenosis consisted of well-formed glands, 11 % of the cases revealed occasional poorly formed glands and/or individual cells which probably represent tangential sections of the small glands of adenosis. In the majority of cases, nuclei are benign appearing without prominent nucleoli. In 73 % of the cases, basal cells were focally identifiable on hematoxylin and eosin (H&E) stained sections. When considering the diagnosis of low grade carcinoma on needle biopsy, one should always question whether a lesion may be adenosis 12 • When the small crowded glands have identical nuclear and cytoplasmic features as surrounding more recognizable glands, then the focus may be adenosis. If one is thinking of diagnosing a nodule of adenosis as cancer, it would be difficult to determine where the "cancer" ends and the benign glands begin, since the small glands of adenosis
merge in with the surrounding more recognizable benign glands. In contrast, glands of carcinoma stand out from surrounding benign glands by their darker cytoplasm, enlarged nuclei, prominent nucleoli and intraluminal contents. Figure 18 shows a nodule of low grade cancer which is homogeneous and does not merge in with adjacent benign glands. The presence of non-branching glands with straight luminal borders is also diagnostic of low-grade cancer (Figure 19). A study of 77 foci of adenosis in needle biopsies found that mitotic figures and blue mucin were uncommon 12 . In needle biopsy specimens, occasional single cells and a minimally infiltrative pattern may be seen in about 12 % of the lesions, crystalloids in 24% of the cases, and some nucleoli in 13% of the foci. Basal cell specific antibodies must be interpreted with caution on needle biopsies. Because basal cell staining may be patchy in adenosis, negative staining in a small focus of glands is not necessarily indicative of malignancy. However, if some of the glands within a crowded glandular focus on needle biopsy demonstrate a basal cell layer, then adenosis can be diagnosed. Because of the difficulty in diagnosing adenosis on needle biopsy, it is useful to verify the diagnosis with high molecular weight cytokeratin antibodies.
Relation of Adenosis to Cancer Although adenosis mimics carcinoma, there is no conclusive evidence suggesting that these patients have an increased risk of harboring or developing adenocarcinoma of the prostate. In our series of adenosis, 14 % of the TUR specimens examined contained incidental foci of adenocarcinoma of the prostate 11 • This is similar to the reported frequency of incidental adenocarcinomas found in TURs performed for clinically benign disease. Prior reports of transitions between adenosis and carcinoma were not verified with the use of basal cell specific antibodies, and may have been adenosis with foci of individual cells, minimal infiltration, or visible nucleoli. Another argument that has been raised to suggest that adenosis is a precursor to prostate cancer is that the two entities share certain morphologic features. Several studies have shown that adenosis may contain acid mucin, crystalloids, nucleoli and have a patchy basal cell layer. Rather than proving a relation between adenosis and carcinoma, these Jindings demonstrate that anyone of these features, by itself, is not specific for carcinoma. For example, acid mucin may be seen in atrophy8, a patchy basal cell layer in clear cell cribriform hyperplasia 1 and nucleoli in basal cell hyperplasia 9• None of these lesions is a precursor to prostate cancer. The interpretation of these features must be made in the context of the totality of a lesion's architectural and cytologic features. A recent study from M.D. Anderson Cancer Center supports the lack of association between adenosis and
•
~':
·r :
Fig. 13. Adenosis with multiple crystalloids (open arrows). Note luminal ruffling in several of the glands which favors adenosis. Also note the presence of a well defined basal cell layer surrounding some of the glands (arrow). Basal cell stains were positive in this case. - Fig. 14. Adenosis labeled with antibodies to high molecular weight cytokeratin showing numerous cytokeratin positive basal cells. - Fig. 15. Adenosis on needle biopsy. The edge of the lesion which has not been transected by the biopsy appears lobular. - Fig. 16. Classic example of adenosis on needle biopsy with benign glands with papillary infolding and branching merging in with small crowded glands with pale-clear cytoplasm. Note corpora amylacea.
'" ,
~ ••:,~ 4 '.
,
....:.. f \,'
'<.....
.
';:\.. I' \to ~ .' •
'.
:".. ; :
r. ~
..
I I , JI
.,
I •
., '
Fig. 17. High magnification of adenosis showing benign appearing glands with papillary infolding and luminal undulations. Admixed crowded glands share nuclear and cytoplasmic features with more recognizable benign glands. - Fig. 18, 20. Low grade adenocarcinoma on needle biopsy. The nodule of adenocarcinoma consists of a uniform population of small glands without branching or papillary infolding (i.e. benign features). This nodule is distinct and does not merge in with adjacent benign larger glands with pale-clear cytoplasm. Note corpora amylacea. - Fig. 19. Low grade adenocarcinoma composed of uniform glands with straight luminal borders. Numerous crystalloids are present.
Adenosis (Atypical Adenomatous Hyperplasia) . 897
nant lesion. In reporting adenosis, it may be helpful to add the following note: "Adenosis, although mimicking adenocarcinoma of the prostate, has not been shown to be associated with an increased risk of carcinoma."
References
Fig. 21. High magnification of adenosis showing benign appearing glands with papillary infolding and luminal undulations. Admixed small crowded glands share nuclear and cytoplasmic features with more recognizable benign glands.
cancer19. They studied 60 prostates from men who underwent cystoprostatectomy for bladder cancer. Fortyone prostates were found to have incidental prostate cancer and 12 were found to have adenosis, which they termed "atypical small glandular proliferations." They subcategorized cases of adenosis into cases with and without architectural and/or cytologic atypia. The overall prevalence of adenosis in prostates with and without carcinoma was not significantly different. The distribution of adenosis with and without atypical features also did not differ significantly between cases with and without carcinoma. There was no topographic association between either form of adenosis and carcinoma. Those studies suggesting a higher risk of carcinoma in men with adenosis have defined it differently, including many examples of what most authorities would call carcinoma s,6. Whether cases of adenosis with more prominent nucleoli differ from more ordinary cases in their association with adenocarcinoma remains unknown. Until long-term follow-up studies are performed to assess the risk of developing adenocarcinoma, adenosis should not be classified as a pre-malig-
1 Ayala AG, Srigley]R, Ro ]Y, Abdul-Karin FW, Johnson DE (1986) Clear cell cribriforming hyperplasia of prostate: Report of ten cases. Am ] Surg Pathol 10: 665 - 71 2 Bostwick DG, Srigley], Grignon D et al. (1993) Atypical adenomatous hyperplasia of the prostate: morphologic criteria for its distinction from well-differentiated carcinoma. Hum Pathol24: 819-832 3 Bostwick DG, Algaba F, Amin MB, Ayala A, Eble ], Goldstein N, Helpap B, Humphrey P, Grignon D, Jones EC, McNeal ], Montironi R, Qian ], Ro ], Srigley ], Tetu B, Troncoso P, True L, Wheeler T, Young RH (1994) Consensus statement on terminology: Recommendation to use atypical adenomatous hyperplasia in place of adenosis of the prostate. Am] Surg Pathol18: 1069-1070 4 Brawer MK, Peehl DM, Stamey TA, Bostwick DG (1985) Keratin immunoreactivity in the benign and neoplastic human prostate. Cancer Research 45: 3663-7 5 Brawn PN (1982) Adenosis of the prostate: A dysplastic lesion that can be confused with prostate adenocarcinoma. Cancer 49: 826 - 833 6 Brawn PN (1983) Interpretation of prostate biopsies. New York: Raven Press, 48-81 7 Epstein ]1 (1989) Disorders of the prostate gland. In: Sternberg SS, ed. Diagnosis in Surgical Pathology. New York: Raven Press, 1293-1432 8 Epstein ]1, Fynheer] (1992a) Acidic mucin in the prostate: can it differentiate adenosis from adenocarcinoma? Human Pathol 23: 1321-1325 9 Epstein ]1, Armas OA (1992b) Atypical basal cell hyperplasia of the prostate. Am] Surg Pat hoi 16: 1205-1214 10 Epstein]1 (1994) Adenosis vs. atypical adenomatous hyperplasia of the prostate. Am] Surg Pathol18: 1070-1071 11 Gaudin PB, Epstein ]1 (1994) Adenosis of the Prostate: Histologic features in transurethral resection specimens. Am] Surg Pathol18: 863-870 12 Gaudin PB, Epstein ]1 1995 Adenosis of the Prostate: Histologic features in needle biopsy specimens. Am J Surg Pathol19: 737-747 13 Hedrick L, Epstein ]1 (1989) Use of keratin 903 as an adjunct in the diagnosis of prostate carcinoma. Am ] Surg Pathol13: 389-96 14 Kramer CE, Epstein ]1 (1993) Nucleoli in low-grade prostate adenocarcinoma and Hum Pathol 24: 618-623 15 Nagle RB, Ahmann FR, McDaniel KM, Paquin ML, Clark VA, Celniker A (1987) Cytokeratin Characterization of Human Prostatic Carcinoma and Its Derived Cell Lines. Cancer Research 47: 281-286 16 Okada H, Tsubura A, Okamura A, Senzaki H, Naka Y, Komatz Y, Morii S (1992) Keratin profiles in normal/hyperplastic prostates and prostate carcinoma. Virchows Archiv A, Pathological Anatomy & Histopathology 421: 157-61 17 O'Malley FP, Grignon D], Shum DT (1990) Usefulness of immunoperoxidase staining with high-molecular-weight cytokeratin in the differential diagnosis of small-acinar lesions of the prostate gland. Virchows Archiv - A, Pathological Anatomy & Histopathology 417: 191-6
898 .
J.
I. Epstein
18 Petersen RO (1992) Urologic Pathology. Philadelphia: J.B. Lippincott 19 Shah lA, Schlageter MO, Stinnett P, Lechago J (1991) Cytokeratin immunohistochemistry as a diagnostic tool for distinguishing malignant from benign epithelial lesions of the prostate. Mod Pathol 4: 220-4
20 Troncoso P, Ayala AG ( 1994) Atypical small gland proliferations of the transition zone in cystoprostatectomy specimens. Mod Pathol 7: 85A 21 Wojno KJ, Epstein Jl (1995) The utility of basal cell specific anti-cytokeratin antibody (34 beta E12) in the diagnosis of prostate cancer: a review of 228 cases. Am J Surg Pathol
Received December 20, 1994 . Accepted in revised form June 10, 1995
Key words: Adenosis - Atypical adenomatous hyperplasia - Adenocarcinoma of the prostate - High molecular weight cytokeratin Jonathan I. Epstein, M.D., Johns Hopkins Hospital, Department of Pathology, 600 N. Wolfe Street, Baltimore, MD 21287, U.S.A.