Case 5 -

Sclerosing Adenosis of the Prostate Hema Samaratunga FRCPA Sullivan Nicolaides Pathology Brisbane , Queensland , Australia

History A 68-year-old male presented in July 2002 with an elevated PSA of 13.19 ng/ml (normal <4.5). His serum PSA had been progressively increasing since 1997, when it was 4.5. He had some associated lower urinary tract symptoms. Digital rectal examination (DRE) revealed a smooth prostate. On transrectal ultrasound (TRUS), the transition zone was enlarged and the volume was estimated to be about 85 g. He underwent a TRUS guided prostatic biopsy in August 2002, and this was reported as benign with chronic prostatitis. He continued to have urinary symptoms and his PSA continued to climb and was up to 16.9 in December 2004 when he underwent a repeat biopsy. This again showed no evidence of malignancy, but had atrophy with acute inflammatory changes. He continued to have obstructive lower urinary tract symptoms and presented for a TURP when 60 g of prostatic tissue was removed. This was reported as nodular prostatic hypertrophy with Gleason score 3+4 = 7 prostatic adenocarcinoma involving < 5% of the tissue. Post operatively, his urinary symptoms improved significantly and his PSA reduced to 3.9. PSA was at about the same level when he was last seen in May 2005. Case 5 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathological Findings About 10 prostate chips displayed a small glandular proliferation. This formed expansile nodules, many of which had a poorly demarcated margin. In some nodules, the margin appeared infiltrative, extending in between collections of benign glands. Very small, very tightly crowded glands formed a large part of the lesion. These were interspersed with larger glands of varying size and shape with some branching, solid nests, cords and single cells. Some glands contained luminal blue mucin. The glandular lining appeared to be a single cell layer with large cells containing abundant finely granular pale eosinophilic cytoplasm. In comparison to those of typical benign glands, these glands had enlarged nuclei with prominent nucleoli. Single cells and cords of cells had similar morphology, but some of these were cuboidal to elongated cells with more eosinophilic cytoplasm. In some areas, a thin layer of hyaline basement membrane material surrounded glands. The background stroma was cellular and partly myxoid. Elsewhere in the gland, there was nodular prostatic hypertrophy. Luminal secretion stained strongly positively with PAS + D and alcian blue. The stroma also showed alcian blue positivity. Immunohistochemical staining revealed widespread strong reactivity for high molecular weight cytokeratin showing an intact basal cell layer. Staining was seen in flattened cells in a basal cell location around glands, in single cuboidal cells and some spindled cells. Diagnosis Sclerosing adenosis of the prostate Discussion Sclerosing adenosis of the prostate is a benign glandular proliferation first described in 1983, when it was thought to represent an adenomatoid tumour. [1]Prostatic acid phosphatase reactivity in lesional cells was taken as evidence of prostatic origin of adenomatoid tumours and thought to confirm the histogenetic heterogeneity of adenomatoid tumours. Since then, immunohistochemical confirmation of presence of basal cells in the lesion has led to the recognition that this is a lesion analogous to sclerosing adenosis of the breast. [2]Due to its composition of small crowded glands, solid nests and single cells and cytologic atypical features, it can closely mimic prostate cancer. In one study, 10% of cases misdiagnosed as prostate cancer were cases of sclerosing adenosis. [3] In spite of its worrisome features, it is benign with no malignant potential. [4] On follow up, no cases have developed malignancy. [3, 4, 5]P resence of widespread high molecular weight cytokeratin positivity confirming presence of basal cells also supports the benign nature of the lesion, as carcinoma usually lacks a basal cell layer. For these reasons, it is also not appropriate to use the term "atypical" for these lesions as some have suggested. [5] It could lead to inappropriate management, as there may be confusion with atypical small acinar proliferations, which need rebiopsy. This lesion has also been labelled fibroepithelial nodules of the prostate, [6] and pseudoadenomatoid tumour. [7] This lesion is most commonly found in the transition zone, therefore appearing predominantly in TURP and radical prostatectomy specimens. The prevalence of sclerosing adenosis in a study by Sakamoto et al was 2%. [5]This was in a series of cases including TURPs, and open and radical prostatectomies. Grignon et al [8] studied a series of radical prostatectomy specimens and also found an incidence of 2%. Sclerosing adenosis may rarely be sampled on needle biopsy. With increasing needle biopsy sampling of the transition zone, it is likely that this lesion will be seen more commonly in needle biopsies. The lesion usually appears incidentally in TURP specimens in patients who present with urinary obstructive symptoms and is usually seen in older patients. It is not known whether sclerosing adenosis contributes to symptoms or elevation of PSA above that caused by BPH in these patients. Usually only one or two small foci of sclerosing adenosis are seen in each case. Rarely, the lesion can be multifocal and many prostate chips can be involved. Lesional size can vary from a few millimetres to more than 1 cm. Typically, these are circumscribed nodular lesions composed of variably sized and shaped, often compressed glands. These are accompanied by epithelial cells in small clusters or singly embedded in a cellular, often myxoid stroma. Larger branching glands are commonly interspersed with tightly crowded small glands, many of which appear to be lined by a single cell layer. Sometimes, small crowded glands are seen merging with or budding off of the larger glands. In rare cases, lesions can appear poorly circumscribed with an infiltrative looking periphery. However, lesional glands are not seen interspersed with normal benign glands. Glandular lumina are usually empty or contain pale eosinophilic secretions. In some cases, luminal blue mucin and even crystalloids can be seen. Usually, cytologic atypia is minimal or absent, but in some cases can be moderate. Nucleoli are often visible but small. In rare cases, nucleoli can be enlarged and prominent. The secretory cells have pale granular of vacuolated cytoplasm. Occasional vacuolated cells can resemble signet ring cells. Other cuboidal to fusiform cells surrounding glands or merging with stroma tend to have more eosinophilic cytoplasm. In some cases, these cells resemble flattened basal cells. A thickened basement membrane is sometimes apparent around glands and cell clusters. Stroma is usually myxoid and contains some collagen and spindled cells resembling fibroblasts. [4, 5, 8] High molecular weight cytokeratin is strongly positive in a basal cell location, within clusters of epithelial cells and spindle cells merging with stroma. These cells are also positive for muscle specific actin and S-100 stains confirming myoepithelial characteristics. PSA and PAP staining is seen within glandular luminal cells and morphologically similar epithelial cells found singly and in small clusters. The most crucial differential diagnosis is obviously with carcinoma. Features including a pseudoinfiltrative appearance of the glandular proliferation in some cases, tightly crowded small glands lined by an apparent single cell layer, presence of single cells, cellular and nuclear enlargement and prominent nucleoli suggest a cancer diagnosis. Luminal blue mucin and crystalloids that are typically found in carcinoma can also suggest a cancer diagnosed. Differentiating this lesion from carcinoma necessitates recognition of the morphological appearances of the lesion. The cellular myxoid stroma of this lesion usually alerts to the correct diagnosis. Prostate cancer typically has normal appearing fibromuscular prostatic stroma and a stromal reaction is often not apparent. In contrast, sclerosing adenosis usually lacks stromal smooth muscle. However, the myxoid stromal appearance of sclerosing adenosis may not be striking in some cases causing diagnostic difficulty. Presence of hyaline eosinophilic basement membrane in some cases, also suggests sclerosing adenosis. This lesion, with poorly formed glands and single cells mimics Gleason score 7 or 8 carcinoma which typically does not form well- circumscribed nodular lesions or present in limited foci unlike most cases of sclerosing adenosis. Glandular structures found in this lesion are similar to those of adenosis with small glands budding off from larger branching glands. Although, prominent nucleoli can be seen in some cases, macronucleoli as seen in some carcinomatous glands are not seen in sclerosing adenosis. Diagnosis of sclerosing adenosis on needle biopsy can be problematic as the entire lesion is not sampled and a nodular appearance may be difficult to appreciate. [9] At least one edge of the lesion can be seen and this may be partially circumscribed. However, the margin can look infiltrative causing concern. Glands that are compressed due to cellular stroma can appear infiltrative and if the nodularity of the lesion is not appreciated in the needle biopsy, misdiagnosis can occur. The distinctive myxoid appearing cellular stroma if present, and the double cell population of pale/ clear cells and eosinophilic cells are features that help in the correct diagnosis. Usually, immunostaining is not necessary for diagnosis. However, in difficult cases, positive staining for high molecular weight cytokeratin, S-100 protein and muscle specific actin is useful as carcinoma is negative for these markers. Other differential diagnostic considerations include adenosis, nephrogenic adenoma (metaplasia), adenomatoid tumour, mesonephric hyperplasia and verumontanum mucosal gland hyperplasia. Presence of a relatively circumscribed glandular proliferation composed of small crowded glands interspersed with larger branching glands, cellular and nuclear enlargement and sometimes prominent nucleoli are also features seen in adenosis. However, in adenosis, there is no stromal sclerosis. Nephrogenic adenoma or metaplasia is another proliferative lesion of the prostate that can superficially mimic sclerosing adenosis and prostate cancer. These lesions are composed of small round to oval, sometime cystic or solid tubules. These lesions involve the prostatic parenchyma, but often involve the lamina propria of the prostatic urethra and can have a papillary component. Tubules are lined by a single layer of cuboidal, flattened or hobnailed cells with clear or eosinophilic cytoplasm. Similar to sclerosing adenosis, some cases display prominent nucleoli. Unlike sclerosing adenosis, these lesions have oedematous and vascularized stroma and stromal hypercellularity and myxoid stroma are not features. Unlike sclerosing adenosis, these lesions are negative for PSA and PAP, but some cases display focal reactivity for high molecular weight keratin. These lesions can be racemase positive and high molecular weight cytokeratin negative. For this reason it can be mistaken carcinoma, unless the diagnosis is made on H&E stains and PSA negativity is demonstrated. [10] There is a superficial resemblance to adenomatoid tumour in some cases. However, the glandular component is clearly prostatic epithelial with numerous PSA and PAP positive cells and not mesothelial as in adenomatoid tumour. Mesonephric remnant hyperplasia is also characterised by a proliferation of single layered tubules. However, in contrast to sclerosing adenosis, they have a lobular arrangement and eosinophilic colloid-like material. Verumontanum mucosal gland hyperplasia is characterised by a small glandular proliferation with "back-to-back" microacini lined by bland cuboidal columnar cells with underlying basal cells. This lesion occurs near the verumontanum and adjacent prostatic urethra. No crystalloids or intra-luminal mucin is seen but intra-luminal corpora amylacea are numerous. [11] The initiating event and pathogenesis of sclerosing adenosis is uncertain. It is thought to involve mesenchymal induction of epithelial cell proliferation, possibly as a result of tissue injury. [4] sclerosing adenosis has been noted within hyperplastic nodules and in association with basal cell hyperplasia [12] with which it shares some histochemical and immunohistochemical features. Normal basal cells of the prostate do not show myoepithelial differentiation, unlike sclerosing adenosis in which basal cells display ultrastructural and immunohistochemical evidence of myoepithelial differentiation. [8, 13] Basal cell myoepithelial characteristics have also been shown in basal cell hyperplasia. [4, 5] Since this lesion has many features of adenosis, it has also been suggested that sclerosing adenosis represents a focus at adenosis that for some reason has undergone stromal sclerosis. In conclusion, sclerosing adenosis is a benign glandular proliferation involving an interplay of transformed basal cells with myoepithelial characteristics, secretory epithelial cells and cellular myxoid stroma with fibroblasts. Knowledge of the morphological spectrum of this lesion should prevent misdiagnosis as cancer. References Chen KTK, Schiff JJ. Adenomatoid prostatic tumor. Urology 1983; 21(1): 88-89. Young RH, Clement PB. Sclerosing adenosis of the prostate. Arch Pathol Lab Med 1987; 111:363-6. Bostwick et al. Overdiagnosis of prostatic adenocarcinoma. Semin Urol Oncol. 1999; 17(4); 199-205. Jones EC, Clement PB, Young RH. Sclerosing adenosis of the prostate gland; a clinicopathological and immunohistochemical study of 11 cases. Am J Surg Pathol 1991: 15 (12): 1171-1180. Sakamoto N et al. Sclerosing adenosis of the prostate. Am J Surg Pathol 1991; 15 (7): 660-667 Sesterhenn IA, Mostofi FK, Davis CJ. Fibroepithelial in nodules of the prostate simulating carcinoma. Lab Invest 1988:51: 83. Hulman G. " Pseudoadenomatoid" tumor of prostate. Histopathol 1989; 14:317-23. Grignon DG et al. Sclerosing adenosis of the prostate gland; A lesion showing myoepithelial differentiation. Am J Surg Pathol 1992; 16 (4): 383-391. Luque RJ et al. Sclerosing adenosis the prostate: Histological features in needle biopsy specimens. Arch Pathol Lab Med 2003; 127:e 14-e 16. Skinnider BF et al. Expression of alpha-methylacyl-CoA racemase (P504S) in nephrogenic adenoma: a significant immunohistochemical pitfall compounding the differential diagnosis with prostatic adenocarcinoma. Am J Surg Pathol. 2004 Jun;28(6):701-5. Gagucas RL et al. Verumontanum mucosal gland hyperplasia. Am J Surg Pathol 1995; 19(1): 30-36. Ronnett BM, Epstein JI. A case showing sclerosing adenosis and an unusual form of basal cell hyperplasia of the prostate. Am J Surg Pathol in 1989; 13:866-72 Sclerosing adenosis of the prostate. Report of three cases with electron microscopy and immunohistochemical study. Histopathology. 1992; 20(6): 505-10.