The Pathology of Benign Hyperplasia

The pathology of benign hyperplasia
by David G. Bostwick, M.D., M.B.A.


Benign enlargement of the prostate (benign prostatic hyperplasia (BPH), nodular hyperplasia, or adenofibromyomatous hyperplasia (AFH)) consists of hyperplastic growth of the epithelium and fibromuscular tissue of the transition zone and periurethral area. Lower urinary tract symptoms (LUTS) are caused by obstruction of urinary flow through the prostatic urethra and interference with muscular sphincteric function. The relationship between prostate volume and clinical symptoms has not been established; however, some studies have identified a weak correlation between the two. This chapter describes the pathologic spectrum of BPH, incuding epithelial and stromal hyperplasia as well as a wide variety of other benign proliferative lesions.

  • Atypical small acinar proliferation suspicious for malignancy

    The minimal criteria for prostatic adenocarcinoma are now sufficiently refined that we can separate out a category of suspicious foci which falls below the diagnostic threshold for malignancy. In 1.5-9.0% of prostate biopsies among unselected series (75-81) there is a localized proliferation of small acini which is suspicious for carcinoma but falls below the diagnostic threshold. Atypical small acinar proliferation (ASAP) is most often due to the small size of the focus. (76) The second most common reason for diagnosing ASAP is lack of definite cytologic evidence for cancer. (76)

    In such cases, the pathologist appropriately should sign the case out as latypical small acinar proliferation suspicious for but not diagnostic. of malignancy (ASAP). We consider this a valid diagnostic category based on our 'absolute uncertainty' regarding the diagnosis. In such cases, the diagnosis of carcinoma cannot be made, but the possibility cannot be definitively excluded. In view of the serious consequences of the diagnosis of carcinoma, it is prudent to render the diagnosis of malignancy only when there is absolute confidence in the histologic findings. On the other hand, we discourage pathologists from using ASAP as a 'wastebasket' diagnosis without first having obtained intradepartmental consultation and, where appropriate, having performed an immunohistochemical stain for the presence of basal cells (keratin 34PE12) or obtaining deeper histologic sections.

    ASAP has a 38%,(81) 42%,(82, 83) 45%,(76) or 60% (79) predictive value for cancer on repeat biopsy, at least equal to that of PIN. Repeat biopsy should be considered, sampling multiple sites of the prostate. Sextant biopsy or greater is best, since sampling only the side or sextant site initially diagnosed as ASAP would have missed cancer in 39% of patients whose cancer was detected exclusively at other sites.

  • Usual epithelial and stromal hyperplasia

    At puberty, the increase in circulating androgens results in a rapid increase in prostatic growth.(1) The normal adult prostate contains about 50% stroma, 30% acinar lumens, and 20% epithelium according to morphometric studies.

    Between 31 and 50 years, hyperplastic tissue grows exponentially, with a doubling time of 4.5 years.(2) From 55 to 70 years, the doubling time for BPH is 10 years, decreasing to more than 100 years in men older than 70 years. The proliferative rate of the epithelium and stroma of BPH is much higher than that of the rest of the prostate (9 and 37 times higher, respectively).(3)

  • Oxidoreductase theory of pathogenesis

    Abnormal activity of certain enzymes may cause BPH by promoting thc retention of tissue DHT, resulting in higher DHT levels. Isaacs et al. found significantly lower concentrations of two enzymes which remove DHT from tissue (17β-liydroxysteroid and 3α-hydroxysteroid reductasc) in BPH patients than in controls.(1)

  • Peripheral zone BPH

    BPH sometimes protrudes from the transition zone into the peripheral zone, creating a palpable abnormality which may be clinically or radiographically mistaken for adenocarcinoma.(26-28) Rarely, fibroadenomatous nodules originate in the peripheral zone and are spatially distinct from the transition zone.(29) These nodules are present in about 2% of radical prostatectomies with cancer and are of unknown etiology. Possible explanations include embryonic reawakening, similar to that proposed for transition zone BPH, parasitic nodule from the transition zone extending into the peripheral zone, and implantation of transition zone tissue in the peripheral zone during embryogenesis. There is no apparent relationship between peripheral zone BPH nodules and cancer.

  • Basal cell hyperplasia

    Basal cell hyperplasia consists of a proliferation of basal cells two or more cells in thickness at the periphery of prostatic acini (Fig. 6.4c).(54-57) It sometimes appears as small nests of cells surrounded by a few concentric layers of compressed stroma, often associated with chronic inflammation. The nests may be solid or cystically dilated, and occasionally are punctuated by irregular rounded luminal spaces, creating a cribriform pattern. Basal cell hyperplasia frequently involves only part of an acinus, and sometimes protrudes into the lumen, retaining the overlying secretory cell layer; less commonly, there is symmetric duplication of the basal cell layer at the periphery of the acinus. The proliferation may protrude into the acinar lumen, retaining the overlying secretory luminal epithelium. Symmetric circumferential thickening of the basal cell layer is less frequent than eccentric thickening, and these changes do not result from tangential sectioning. The basal cells in basal cell hyperplasia (BCH) are enlarged, ovoid or round, and plump (epithelioid), with large pale ovoid nuclei, finely reticular chromatin; and a moderate amount of cytoplasm. Nucleoli are usually inconspicuous (less than 1 µm in diameter) except in atypical BCH (see below). It is rarely associated with atypical adenomatous hyperplasia.

  • Morphometry of BPH: ratio of epithelium and stroma

    Numerous techniques have been used to study the ratio of epithelium and stroma in BPH, including light microscopy,(33) computer-assisted digital image analysis,(34, 35) stereologic analysis,(36) and texture analysis.(37) The relative amounts of epithelium and stroma are 21.6-40% for epithelium and 60-78.4% for stroma, respectively, although this may differ between races.(6) Japanese men have overall greater glandular lumen and lower stromal components as well as lower stroma to epithelium and stroma to glandular ratios than either Caucasian or African-American men. Mean per cent area densities of stroma and epithelium were 77.4 and 15.2%, compared to 84.2 and 12.1% for Caucasian men and 84.4 and 12.4% for African-American men, respectively. This may have a bearing on differences in PSA levels and overall clinical BPH prevalence. The clinical importance of the ratio of epithelium and stroma is that men with symptomatic BPH have a significantly higher proportion of stroma than men with asymptomatic BPH.(34) It is likely that the predominant component of the BPH nodule determines the response to therapy: smooth muscle-predominant nodules would respond to α-blockers, epithelial nodules to androgendeprivation therapy (LHRH agonists, steroid anti-androgens and 5α-reductase inhibitors) and fibrous nodules to surgery.

  • Pathology of BPH

    Grossly, BPH consists of variably sized nodules that are soft or firm, rubbery, and yellow-gray, and bulge from the cut surface upon transection (Fig. 6.2). If there is prominent epithelial hyperplasia in addition to stromal hyperplasia, the abundant luminal spaces create soft and grossly spongy nodules that ooze a pale-white watery fluid. If BPH is predominantly fibromuscular, there may be diffuse enlargement or numerous trabeculations without prominent nodularity Degenerative changes include calcification and infarction. BPH usually involves the transition zone, but occasionally nodules arise from the periurethral tissue at the bladder neck. Protrusion of bladder neck nodules into the bladder lumen is referred to as median lobe hyperplasia (Fig. 6.2). Rarely, hyperplastic nodules are present in the peripheral zone. Microscopically, BPH is invariably nodular, comprising varying proportions of epithelium, fibrous connective tissue, and smooth muscle. There are five types of nodules, including adenomyofibromatous (most common), fibromuscular, muscular (uncommon), fibroadenomatous, and stromal (Fig. 6.3). In practice, pathologists do not subclassify BPH histologically because of the wide variation in composition. Common associated findings include chronic inflammation, acinar atrophy, and luminal corpora amylacea and microcalculi. The transition zone is infrequently sampled by needle biopsy unless the urologist specifically targets this area or there is massive BPH, which compresses the peripheral zone. The diagnosis of BPH is often used by pathologists in reporting the findings in needle biopsy specimens when only normal benign peripheral zone tissue is present. However, such findings should be referred to as 'benign prostate tissue' as histologic biopsy results do not correlate with BPH, except when stromal nodules are present.(25) We require the presence of at least part of a nodule for the diagnosis of BPH. Narrow 18-gauge biopsies virtually never contain the entire nodule unless it is very small and fortuitously sampled. Casual use of the term BPH for benign prostatic tissue may mislead the urologist into believing that a palpable nodule or hypoechoic focus of concern has been sampled and histologically evaluated; it is important for the pathologist to correlate the light microscopic findings with the clinical impression, so communication with the urologist is vital.

    Vascular insufficiency probably accounts for infarction of BPH nodules, seen in up to 20% of resected cases (Fig. 6.3). The center of the nodule undergoes hemorrhagic necrosis, often with reactive changes in the residual epithelium at the periphery, including squamous metaplasia and transitional cell metaplasia.

  • Histologic variants of hyperplasia and associated benign lesions

    There is a wide morphologic spectrum of epithelial and stromal hyperplasia. Awareness of these variants is important in order to avoid misdiagnosis of adenocarcinoma (Table 6.2).

  • Clinical significance of AAH

    Three significant unanswered questions remain regarding AAH. First, does 'atypical small acinar proliferation of uncertain significance' represent underdiagnosed adenocarcinoma? Six of eight cases in one study created considerable diagnostic discord among the participants.(63) Critics could reasonably argue that the lack of concordance for this lesion indicates that it is not a distinct entity but merely a reflection of our uncertainty; also, the criteria for distinguishing this lesion from AAH and cancer may be difficult to apply in practice.

    Second, does Gleason primary grade 1 adenocarcinoma represent overdiagnosed adenocarcinorna? These lesions are uncommon; most would agree that Gleason primary grade 2 adenocarcinoma (infiltrating acini) is malignant, but what is the true biological potential of the circumscribed uniform proliferation of Gleason primary grade 1 adenocarcinorna? It is likely that many or most of the original grade 1 cancers would be classified today as AAH.

    Third, is AAH a precursor of adenocarcinorna? AAH has been proposed as a premalignant 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 autopsy), topographic relationship with small-acinar carcinoma, age at peak incidence that precedes that of carcinoma, increasing silver-stained nucleolar organizer regions (AgNOR) 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 and hyperplastic prostatic epithelium. Some authors 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.(70, 71) However, we have recently demonstrated allelic imbalances at microsatellite polymorphic markers on a number of chromosomes in 47% of cases of AAH.(72) These genetic alterations are present frequently in high-grade PIN and cancer.(73, 74) AAH may be related to the subset of cancers that arise in the transition zone in association with BPH.(5, 74) Although the biological significance of AAH is slight, its light microscopic appearance and immunophenotype allow it to be separated from carcinoma.

  • Association of BPH and prostate cancer

    There are a number of similarities between BPH and cancer(5) (Table 6.1). Both display a parallel increase in prevalence with patient age according to autopsy studies, although cancer lags by 15-20 years. Both require androgens for growth and development, and both may respond to androgen-deprivation treatment. Most cancers arise in prostates with concomitant BPH, and cancer is found incidentally in a significant number (10%) of transurethral prostatectomy specimens.

    In addition, serum PSA levels have been shown to correlate with prostatic epithelial volume(38) and it is thought that BPH may be related to prostate cancer arising in the transition zone. Increased levels of stromal components (smooth muscle cells and connective tissue) have been identified in the transition zone of BPH patients.(39, 40)

    Investigation of the stromal components of prostate cancer tissue showed a correlation between cancer in the peripheral zone and a decrease in smooth muscle cells and an increase in collagen fibers. As cancer grade increased, the ratios between the two became more pronounced.(41)Although the exact association between prostate cancer and BPH remains undefined, low-grade carcinomas have been found to resemble BPH tissue in the transition zone.(40) A proposed molecular marker for prostate cancer, α-methylacyl-CoA racemase (AMACR), which is found in prostatic intraepithelial neoplasia (PIN) and peripheral zone prostate carcinomas, has been observed in BPH tissue located adjacent to cancerous cells. Staining for the monoclonal antibody against AMACR (P504S), plus P63 or antikeratin 34βE12 antibodies revealed areas of transition from hyperplasia to carcinoma in some BPH nodules. This suggests that some BPH nodules containing AMACR may give rise to transition-zone carcinomas and that upregulation of AMACR occurs prior to neoplastic transformation. The findings also suggest that fatty acids, the oxidation of which AMACR is involved in, contribute to the development of carcinoma in the transition zone. Although BPH is not generally considered a premalignant lesion or a precursor of carcinoma, fast-growing BPH has been linked to increased risk of clinical prostate cancer. Rapidly progressing BPH was found to be more common in men with noninsulin-dependent diabetes mellitus, hypertension, obesity, dyslipidemia, atherosclerosis, hyperuricemia, hyperinsulinemia, and elevated alanine aminotransferase (ALAT). The increased levels of pronounced clinical prostate cancer identified in these men may therefore arise as a function of insulirl production.(42) PSA levels have also been found to increase in a linear fashion alongside glandular proliferation and are significantly greater in cases of BPH with chronic prostatitis than BPH without chronic prostatitis. The relevance of these findings as regards risk of prostate cancer development, however, is as yet unknown.(43)

    The optimal number of chips to submit for histologic evaluation from a transurethral resection specimen remains controversial, with some authors preferring partial sampling and others advocating complete submission even with large specimens, which would require many cassettes.(44-47) The Cancer Committee of the College of American Pathologists recommends a minimum of six cassettes for the first 30 g of tissue and one cassette for every 10 g thereafter.(48)

  • Sclerosing adenosis

    Sclerosing adenosis of the prostate, originally described as adenomatoid or pseudoadenomatoid tumor, consists of a benign circumscribed proliferation of small acini set in a dense spindle cell stroma (Fig. 6.4h). (84-90) It is an incidene tal finding in transurethral resection specimens for BPH, present in about 2% of specimens; rare cases are associated with elevated serum PSA levels. Sclerosing adenosis is usually solitary and microscopic, but may be multifocal and extensive.

    The acini are predominantly well formed and small to medium in size, but may form minute cellular nests or clusters with abortive lumens. The cells lining the acini display a moderate amount of clear to eosinophilic cytoplasm, often with distinct cell margins. The basal cell layer may be focally prominent and hyperplastic, particularly in acini thickly rimmed by paucicellular hyalinized stroma. In some areas, the acini merge with the exuberant stroma composed of fibroblasts and loose ground substance. There is usually no significant cytologic atypia of the epithelial cells or stromal cells, but we have recently encountered several cases with moderate to severe cytologic atypia.

    Sclerosing adenosis can be distinguished from adenocarcinoma by its distinctive fibroblastic stroma which is rarely seen in carcinoma; benign cytology, with epithelial cells and stromal cells which lack the prominent nucleomegaly and nucleomegaly is usually seen in prostatic carcinoma; hyalinized periacinar stroma occasionally seen in sclerosing adenosis; intact basal cell layer; frequent association with BPH; and immunophenotype of S-100 protein and actin immunoreactivity.

    The unique immunophenotype of sclerosing adenosis is a valuable diagnostic clue in distinguishing it from adenocarcinoma. Unlike normal prostatic epithelium or carcinoma, basal cells in sclerosing adenosis show positivity for S-100 protein and smooth muscle actin, reflecting their myoepithelial differentiation; consequently, sclerosing adenosis is considered a form of metaplasia. The basal cell layer is intact or fragmented in sclerosing adenosis, as demonstrated with immunohistochemical stains for high molecular weight keratin 34βE12, compared with absence of staining in carcinoma. PSA and PAP are present with secretory luminal cells. Acid mucin stain may also be of value in separating sclerosing adenosis from carcinoma; however, acid mucin is not specific for malignancy.Ultrastructural studies confirm the presence of myoepithelial differentiation in sclerosing adenosis, with collections of thin filaments and dense bodies. (86)

  • Giant BPH (giant prostatic hyperplasia)

    Prostatic enlargement due to BPH rarely exceeds 100 g, which occurs in only 4% of men over 70 years of age (Fig. 6.3).(2) Giant BPH is arbitrarily defined as specimens over 200 g(30) or 500 g;(31) the lower threshold was suggested by Japanese authors,(30) probably because BPH is rare in their country. The largest adenoma ever removed by suprapubic prostatectomy weighed 820 g, but the patient died of hemorrhage.(32) Giant BPH tends to have the typical adenomyofibromatous pattern.

  • Androgen/aging theory of BPH pathogenesis

    As men age, there is an increase in cumulative lipid peroxidation, resulting in an increase in tissue concentration of co-factors such as NAD and NADPH. This, in turn, increases 5α-reductase concentration (which is sensitive to changes in NADPH) and levels of prostatic DHT, which is reduced from testosterone by the enzyme. Two types of 5α-reductase have been identified-type 2 is the isoform predominantly active in the prostate, while type 1 is mainly located in the skin and liver. The increase in DHT ultimately induces epithelial and stromal growth, which culminates in BPH. The androgen aging theory of BPH pathogenesis is supported by the consistent observation of high levels of DHT in patients with BPH, and the reduced levels of DHT, and BPH symptoms, with 5α-reductase inhibition.(13)

  • Atrophy and postatrophic hyperplasia (postinflammatory hyperplasia; partial atrophy; postsclerotic hyperplasia)

    Atrophy is a common microscopic finding, consisting of small, distorted glands with flattened epithelium, hyperchromatic nuclei, and stromal fibrosis. It is usually idiopathic, and the prevalence increases with advancing age.(23) At low magnification, atrophy may be confused with adenocarcinoma due to the prominent acinar architectural distortion. At high magnification, atrophy usually lacks nuclear and nucleolar enlargement, except in cases of postatrophic hyperplasia.

    Clusters of atrophic prostatic acini which display proliferative epithelial changes are referred to as postatrophic hyperplasia (PAH).(50, 51) PAH is at the extreme end of the morphologic continuum of acinar atrophy, which most closely mimics adenocarcinoma. This continuum varies from mild acinar irregularity with a flattened layer of attenuated cells with scant cytoplasm to that of PAH in which the lining cells are low cuboidal with moderate amounts of cytoplasm. There is no sharp division in thiscontinuum between atrophy and PAH, challenging the utility of PAH as a distinct entity. However, the morphologic mimicry of PAH and carcinoma creates the potential for misdiagnosis, sometimes resulting in unnecessary prostatectomy.(51) To avoid this potentially tragic misinterpretation, the pathologist should have an understanding of this extreme morphologic variant of atrophy. We believe that PAH is a diagnostic category for atrophic acini, which most closely mimic adenocarcinoma, recognizing that this is merely a descriptive term.

    PAH consists of a microscopic lobular cluster of five to 15 small acini with distorted contours reminiscent of atrophy (Fig. 6.4a). One or more larger dilated acini are usually present within these small round to oval clusters, and the small acini appear to bud off from the dilated acinus, imparting a lobular appearance to the lesion. The small acini are lined by a layer of cuboidal secretory cells with mildly enlarged nuclei with an increased nucleus-to-cytoplasmic ratio when compared with adjacent benign epithelial cells. The nuclei contain finely granular chromatin, and nucleoli are usually small, although mildly enlarged nucleoli are focally present in 39% of cases. The cytoplasm is often basophilic or finely granular to clear, and luminal apocrine-like blebs are present in 33% of cases. Luminal mucin is occasionally present in PAH. Corpora amylacea are present in 75% of cases of PAH, but crystalloids are rarely if ever seen.

    The basal cell layer is usually present in PAH, but is often inconspicuous by routine light microscopy. Basal cell hyperplasia is rarely seen in foci of PAH. Immunohistochemical stains for high molecular weight keratin (antibody 34βE12) reveal a focally fragmented basal cell layer in some cases. Adjacent prostatic acini always show at least focal atrophy.

    Stromal changes are always present in PAH, ranging from smooth muscle atrophy to dense sclerosis with compression of acini. In cases with sclerosis, the acinar lumens are compressed and showed marked distortion. Subtyping of PAH into the lobular and postsclerotic subtypes is useful only to allow recognition of PAH and distinguish it from mimics such as low-grade adenocarcinoma, and we prefer not to subtype PAH. Also, PAH is often associated with patchy chronic inflammation; infrequently, dilated acini contain luminal neutrophils. PAH is distinguished from carcinoma by its characteristic lobular architecture, intact or fragmented basal cell layer, inconspicuous or mildly enlarged nucleoli, and adjacent acinar atrophy with stromal fibrosis or smooth muscle atrophy. Low-grade adenocarcinoma is the most important differential diagnostic consideration with PAH. PAH usually has a lobular pattern on low power, similar to Gleason pattern 2 and 3 adenocarcinoma. However, the lobular pattern is less distinct in cases with abundant stromal sclerosis, and there may be a pseudoinfiltrative growth pattern with fibrous entrapment of acini. Nucleolar changes are also useful in separating PAH and carcinoma, although some cases of low-grade carcinoma have only patchy large nucleoli or even micronucleoli. Mildly enlarged nucleoli may be present in PAH, but only focally, and the majority of cells have micronucleoli. The separation of PAH from carcinoma is most difficult in needle biopsy specimens in which only a portion of the lesion is sampled, and awareness of this entity assists in this distinction. In about half of the biopsies containing PAH, the lesion extends to the edge of the tissue core, indicating incomplete sampling.

  • Immunohistochemical findings

    Basal cell hyperplasia (typical and atypical forms) displays intense cytoplasmic immunoreactivity in virtually all of the cells with high molecular weight keratin 34βE12. Immunoreactivity for PSA, prostatic acid phosphatase (PAP), chromogranin, S-100 protein, and neuron-specific enolase is present in rare basal cells in the majority of cases.

  • Pathogenesis of BPH

    The prevalence of histologic BPH increases rapidly from the fourth decade of life, and over 70% of men are affected by their seventh decade.(5) although differences in cellular composition between some races have been observed.(5)

    Epidemiologic studies have shown that the risk of undergoing prostatectomy for BPH is 4-fold greater in first-degree relatives of young men with BPH than in controls. (7) The concordance rate for BPH among identical (monozygotic) twins is greater than among nonidentical twins (dizygotic), suggesting a hereditary influence in BPH.(8)

    Development of BPH includes three pathologic stages: nodule formation, diffuse enlargement of the transition zone and periurethral tissue, and enlargement of nodules.(9-11) In men under 70 years of age, diffuse enlargement predominates; in older men, epithelial proliferation and expansile growth of existing nodules predominate, probably as the result of androgenic and other hormonal stimulation. This is accompanied by the clinical symptoms of LUTS and reduced peak urinary flow rates, which correlate with prostate volume and postvoid residual volume, and have also been linked to prostate-specific antigen (PSA) levels.(12)

    The pathogenesis of BPH is uncertain, and multiple overlapping theories have been proposed, all of which may be operative.(13-14) Essential to all are advancing age and the presence of circulating androgens. That regression of BPH can be reversibly induced by luteinizing hormonereleasing hormone (LHRH) agonists, and the lack of BPH in men deficient in dihydrotestosterone (DHT), indicate that androgens have at least an important supportive if not causative role in the development of BPH.

  • Estrogen theory of pathogenesis

    The ratio of plasma estrogen to testosterone increases with age, and this may result in excessive stromal growth because of the greater number of hormone receptors in the stroma compared with the epithelium. Investigation of the distribution of estrogen receptors alpha and beta (ERα and ERβ) revealed that ERα was only found in the stromal cells of the peripheral zone while ERβ was present in the stroma and the epithelium of both the peripheral and transition zones.(16) This suggests a powerful influence of estrogen, acting through ERβ, on BPH development and helps explain why BPH is chiefly a stromal disease. Attempts to correlate the amount of BPH with serum hormone concentrations have yielded conflicting results,(17) although testosterone and estrogen are clearly influential.

  • Hyperplasia of mesonephric remnants

    Hyperplasia of mesonephric remnants in the prostate and periprostatic tissues is a rare and benign mimic of adenocarcinoma which is usually identified in transurethral resection specimens. According to Gikas et al (92) it shares many features with mesonephric hyperplasia of the female genital tract, including apparent infiltration of the stroma and neural spaces, lobular arrangement of small acini or solid nests lined by a single cell layer, prominent nucleoli, and eosinophilic intratubular material.

    Two histopathologic patterns have been described, both with a lobular pattern and cuboidal cell lining. One pattern consists of small acini which contain colloid-like material, reminiscent of thyroid follicles. The lining consists of a single layer of cuboidal cells without significant cytologic atypia. The second pattern consists of small acini or solid nests of cells with empty lumens, reminiscent of nephrogenic metaplasia. Unlike prostate cancer, the acini of prostatic mesonephric remnant contain a small amount of cytoplasm and this may be the most useful diagnostic finding. Also, the acini may be atrophic or exhibit micropapillary projections lined by cuboidal cells. Prominent nucleoli are occasionally observed, compounding the diagnostic confusion. The acini display immunoreactivity for keratin 34βE12, but not for PSA or PAP One of the original cases was misdiagnosed as adenocarcinoma, resulting in unnecessary prostatectomy.

  • Cribriform hyperplasia

    Cribriform hyperplasia, including clear cell cribriform hyperplasia, consists of a nodule composed of glands arranged in a distinctive cribriform pattern (Fig. 6.40f). The cells from such glands usually have pale to clear cytoplasm and small uniform nuclei with inconspicuous nucleoli.(61, 62) This lesion is distinguished from high-grade PIN and carcinoma by the lack of prominent nucleoli in acinar cells.

  • Atypical adenomatous hyperplasia (adenosis)

    Atypical adenomatous hyperplasia (AAH) is a localized proliferation of small acini within the prostate that may be mistaken for carcinoma (Fig. 6.4g).(63-65) Small acinar 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. The greatest difficulty in distinguishing AAH from carcinoma is with lesions containing nucleoli intermediate in size between benign and malignant. To accommodate this borderline group, we recommend separating small acinar proliferations into AAH (probably benign) and atypical small acinar proliferations suspicious for, but not diagnostic of, malignancy (possibly benign, but having some features of carcinoma) (see below). AAH varies in incidence from 19.6% (transurethral resection specimens) to 24% (autopsy series in 20- to 40- year-old men).(65, 66) It can be found throughout the prostate, but is usually present near the apex and in the transition zone and periurethral area.(63)

  • Atypical BCH

    Atypical BCH is identical to BCH except for the presence of large prominent nucleoli (Fig. 6.4d). The nucleoli areround to oval and lightly eosinophilic. There is chronic inflammation in the majority of cases, suggesting that nucleolomegaly is a reflection of reactive atypia. A morphologic spectrum of nucleolar size is observed in basal cell proliferations, and only those with more than 10% of cells exhibiting prominent nucleoli are considered atypical.(54)

  • Role of basal cells

    Basal cells may act as 'reserve' cells, which are capable of dividing and replenishing the prostatic epithelium, including the ability to differentiate into other cell types such as secretory cells.(58) Basal cells apparently retain the ability to undergo metaplasia, including squamous differentiation in the setting of prostatic infarction and myoepithelial differentiation in the setting of sclerosing adenosis. Epidermal growth factor receptors have been identified in basal cellsbut not in secretory cells, suggesting that these cells play a role in growth regulation.(59, 60)

  • Verumontmum mzkcosal gland hyperplasia

    This is an uncommon form of small acinar hyperplasia which mimics well-differentiated adenocarcinoma (92) It is invariably small, less than 1 min, often multicentric, and limited anatomically to the verumontanum, utricle, ejaculatory ducts, and adjacent prostatic urethra and ducts. The acini are small and closely packed, with an intact basal cell layer, small uniform nuclei, and inconspicuous nucleoli. The basal cells display iinmunoreactivity for high molecular weight keratin and are S-100 protein negative. This lesion is rare in needle biopsies and is almost never sampled in transurethral resections because of the sparing of the verumontanum by this procedure.

  • Separation of AAH and cancer

    AAH is distinguished from well-differentiated carcinoma by the following: (1) inconspicuous nucleoli, (2) infrequent crystalloids, and (3) fragmented basal cell layer as seen with basal cell-specific anti-keratin antibodies. All measures of nucleolar size allow separation of AAH from adenocarcinoma, including mean nucleolar diameter, largest nucleolar diameter, and percentage of nucleoli greater than 1 µm in diameter. There is apparently widespread acceptance of Gleason's criterion of nucleolar diameter greater than 1 µm for separating well-differentiated cancer (Gleason primary grades 1 and 2) from other proliferative lesions.(67)

    Despite the utility of these features, the absolute distinction between AAH and carcinoma is still problematic in some cases, particularly in those cases that are classified as atypical small acinar proliferations of uncertain significance. Other morphologic features are not useful in distinguishing AAH from adenocarcinoma, including lesion shape, circumscription, multifocality, average acinar size, variation in acinar size and shape, chromatin pattern, and the amount and tinctorial quality of the cytoplasm. Both lesions contain acidic mucin in the majority of cases.(68, 69)

  • Stromal hyperplasia with atypical giant cells

    Stromal hyperplasia with atypia consists of stromal nodules in the setting of BPH with increased cellularity and nuclear atypia (Fig. 6.4b).(52, 53) These may appear as solid stromal nodules (often referred to as atypical leiomyoma) or with atypical cells interspersed with benign glands.

    Stromal nuclei are large, hyperchromatic with smudged chromatin, and rarely multinucleated or vacuolated, with inconspicuous nucleoli. There are no mitotic figures and no necrosis. Stromal hyperplasia with atypia has no malignant potential, and the atypical cells are considered degenerative.

  • Inflammationl/growth factor theory of pathogenesis

    Inflammation and the release of locally produced growth factors such as platelet-derived growth factor (PDGF), fibroblast growth factors (FGF), insulin-like growth factors and transforming growth factor beta (TGFβ) may play a role in the development of BPH due to effects on cell proliferation, apoptosis, and extracellular matrix turnover.(18-19) FGF-7 and FGF-2 are overexpressed in hyperplastic prostate tissue in comparison to normal epithelium and transition zone tissue.(20) There is a marked reduction in basic FGF level in BPH treated with finasteride in comparison with untreated BPH.(21) Steiner et al.(22) found that the number of T-cells in BPH is greater than that in the normal prostate, and these T-cells are preactivated and functionally capable of producing sufficient amounts of autocrine growth factors necessary for Tcell proliferation.

    Analysis of almost 4000 histologic BPH samples revealed that inflammation was present in over 40% of cases, with a correlation observed between this factor and prostate volume.(23) Conversely, however, Helpap showed that there is no significant correlation between the amount of chronic inflammation and the extent of BPH.(24)

  • Immunohistochemistry of AAH

    Immunohistochemistry is often useful in the diagnosis of AAH. The basal cell layer is characteristically discontinuous and fragmented in AAH, but absent in cancer, a feature that can be demonstrated in routine formalin-fixed sections with basal cell-specific anti-keratin (high molecular weight keratin antibodies (34βE12)).

  • Basal cell adenoma

    Basal cell adenoma consists of a large, round, usually solitary, circumscribed nodule of acini with basal cell hyperplasia in the setting of BPH (Fig. 6.4e). The nodule contains uniformly spaced aggregates of hyperplastic basal cells which form small solid nests or cystically dilated acini. Condensed stroma is seen at the periphery of the nodule. In addition, stromal connective tissue traverses the adenomatous nodule, creating incomplete lobulation in some cases. Stroma is normal or slightly increased in density, and may be basophilic without myxoid change adjacent to cell nests.

    The basal cells in basal cell adenoma are plump, with large nuclei, scant cytoplasm, and usually inconspicuous nucleoli, although large prominent nucleoli are rarely observed. Many cells are cuboidal or 'epithelioid', particularly near the center of the cell nests, and some contain clear cytoplasm. Prominent calcific debris is often present within acinar lumens.

    Multiple basal cell adenomas are referred to as basal cell adenomatosis. Basal cell adenoma invariably arises in association with BPH, and appears to be a variant.

  • Embryonic reawakening theory of pathogenesis;

    McNeal(10,11) suggested that the earliest lesion of BPH is a proliferation of epithelium, probably under the influence of DHT, with branching and budding due to 'reawakening' of the embryonic inductive potential of the prostatic stroma during adulthood. This theory accounts for the presence of the common fibroadenomatous nodules of BPH.

  • Basal cell hyperplasia and basal cell proliferations

    There are three patterns of benign basal cell hyperplasia, including typical basal cell hyperplasia (Fig. 6.4c), atypical basal cell hyperplasia (Fig. 6.4d), and basal cell adenoma (Fig. 6.4e).(54,55)



BPH is one of the most common diseases in elderly men, but its etiology and pathogenesis remain uncertain. The pathologic features of BPH are well defined and heterogeneous, and include varying amounts of epithelium, smooth muscle, and fibrous stroma. The correlation of pathologic findings and clinical symptoms is weak, although recent evidence suggests that men with symptomatic BPH have a significantly higher proportion of stroma than men with asymptomatic BPH. There is also increasing evidence of a relationship between BPH and the development of prostatic carcinoma. The tissue elements in BPH may respond differently to various forms of therapy. Numerous interesting and unusual pathologic variants of BPH have been described which mimic adenocarcinoma clinically and pathologically.


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