Case 3 -

Phyllodes Tumor of the Prostate Gland Edward C. Jones MD, FRCPC Vancouver Hospital and University of British Columbia Vancouver, BC, Canada

Clinical History: A 48-year-old man presented with obstructive renal failure secondary to an enlarged prostate gland. After treatment by transurethral curettage, the patient was lost to follow-up for two years when he presented with recurrent renal failure. A CT scan demonstrated a markedly enlarged, inhomogeneous, lobulated prostate with cystic and solid areas. The seminal vesicles were not identified. There was no pelvic lymphadenopathy. At the time of the repeat transurethral curettage, 23 grams of tissue were removed. Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathological Findings: The submitted slide, a section from the most recent operation, demonstrates a diffuse proliferation of cystic glands and elongated glands with slit-like spaces. The glands are distorted and compressed by a cellular proliferation of plump oval to spindled stromal cells. Broad stromal polypoid processes push into the gland spaces. There is variable stromal cellularity with cellular tracts and occasional small nodules of spindle cells between the glandular elements, alternating with areas of sclerosis and patchy edema. An alcian blue stain at pH 2.5 identifies foci of stromal acid mucin, predominantly in the sub-epithelial zone. The stromal spindle cells lack mitotic activity and nuclear anaplasia, although an occasional enlarged hyperchromatic smudged nucleus is present. Heterologous stromal elements are absent. The epithelium is hyperplastic with foci of papillary tufting and cribriform pattern. An occasional focus of squamous metaplasia is present. The cysts are lined by columnar to low-cuboidal epithelium. A basal cell layer is apparent in most of the glands. A PAS stain demonstrates abundant glycogen within the stromal cell cytoplasm and, to a lesser extent, within the epithelium. The prostatic tissue from the previous transurethral curettage had similar histological findings. Immunohistochemical study reveals diffuse, strong immunoreactivity for muscle-specific actin and desmin, with no reactivity for S-100 or cytokeratin, within the spindle cells. This correlates with the reported ultrastructural evidence of stromal smooth muscle differentiation [1]. The stromal cells are variably positive for vimentin. The cytokeratin immunostain highlights a near continuous layer of basal cells beneath the epithelial secretory cells. The latter are strongly positive for prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP). An occasional chromogranin-positive and a rare serotonin-positive epithelial cell are present. Flow cytometric DNA content analysis reveals a diploid tumor. Diagnosis: Low grade phyllodes tumor of the prostate Discussion: Phyllodes tumor of the protate gland is a rare lesion that has been referred to by a variety of terms, including prostatic cystic epithelial-stromal tumor [2], phyllodes type of atypical prostatic hyperplasia [3], cystadeno-leiomyofibroma [4], and cystosarcoma phyllodes of the prostate [5]. It typically presents with a urinary obstruction, hematuria, or dysuria. There may be severe obstruction, often occurring at an age when symptomatic prostatic hyperplasia would be unexpected. The youngest reported case is that of a 22-year old man who had a 20 cm retrocystic mass [2]. Most reported tumors range from 4 cm to 25 cm [1, 2, 3, 4, 5, 8, 9, 10], but there is one report of a 58 cm tumor weighing 11.2 kg [7]. The tumor can arise centrally from the verumontanum region [8, 9] or it can involve one side of the gland more peripherally [2, 3, 5]. At the time of transurethral curettage the urologist may note an unusual spongy of cystic texture of the tissue [5]. The diagnosis is usually made on curetted tissue, as it may be overlooked on needle biopsy, in which it is difficult to appreciate the distinctive architecture of the tumor. Even in curetted tissue, a low grade tumor may blend with otherwise unremarkable hyperplastic nodules, leading to under diagnosis. The major clue to the diagnosis is the presence of a diffuse proliferative process with an unusually cellular stroma lying between, and invaginating into, cysts and compressed elongated glands. Analogous to phyllodes tumor of the breast, phyllodes tumor of the prostate may exhibit a spectrum of low to high grade histological features [1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 25, 26, 27]. A high-grade tumor is recognized by an elevated stromal-epithelial ratio with increased stromal cellularity and overgrowth, marked cytologic atypia, increased mitotic activity, and necrosis [1, 6]. A sarcomatous component may consist of a solid nodule that grossly contrasts with the cystic areas of a co-existent low-grade tumor [5], or it may be admixed with the glandular component [10]. A sarcomatous component may arise within a low-grade tumor over time [1, 6, 10], often after multiple recurrences over many years [6]. There is a report of a phyllodes tumor of the prostate containing an incidental focus of well-differentiated prostatic adenocarcinoma [7]. The differential diagnosis of phyllodes tumor of the prostate includes prostatic stromal hyperplasia with bizarre nuclei [11, 21, 22], leiomyoma with or without cytologic atypia [20, 21, 22], giant multiocular prostatic cystadenoma [12], benign prostatic hyperplasia with cystic glands and other benign cysts such as mullerian duct cysts and congenital or acquired seminal vesicle cysts [13]. Of note, phyllodes tumor may arise in the seminal vesicle as a supraprostatic mass with an epithelial component that is PSA and PAP negative [14, 24]. Prostatic stromal hyperplasia with bizarre nuclei is a hypocellular lesion with enlarged hyperchromatic degenerative appearing nuclei dispersed between ordinary hyperplastic glands or within nodules of stromal hyperplasia [13], without mitotic activity. Leiomyoma [20, 21, 23], perhaps arbitrarily distinguished from a hyperplastic stromal nodule simply by its large size, will typically have interlacing fascicles of bland smooth muscle cells forming a discrete, circumscribed nodule without a glandular component, as seen in leiomyomas found at other sites, such as the uterus. Atypical leiomyoma or leiomyoma with bizarre nuclei may occur in the prostate. These lesions may be referred to as atypical smooth-muscle tumor of uncertain behavior as the criteria to distinguish between benign and malignant smooth muscle tumors of the prostate are not as well defined as they are in the uterus [20, 21, 22]. Giant multilocular cystadenoma of the prostate is a tumor with cysts lined by prostate-type epithelium surrounded by dense fibrous stroma. A cystic adenoma of the prostate characterized by a complex inward growth of papillary epithelial fronds with little stroma has also been described [15]. Phyllodes tumor of the prostate may show exuberant glandular hyperplasia, a feature that may lead to misinterpretation if the stromal component is overlooked [28]. Benign prostatic hyperplasia commonly contains small cystic glands within easily recognized hyperplastic nodules. One should not over interpret the small fibradenoma-like foci that may be uncommonly found in otherwise unremarkable cases of prostatic nodular hyperplasia [16]. Mullerian duct cysts (typically midline lesions) and seminal vesicle cysts (typically lateral lesions) are usually unilocular cysts that lack the prostatic epithelial lining and the stromal cellularity of a prostatic phyllodes tumor [13]. If the biphasic nature of a phyllodes tumor is not recognized, a number of spindle cell lesions known to rarely involve the prostate, such as post-operative spindle cell nodule, inflammatory myofibroblastic proliferations, nerve sheath tumors, fibromyxoma , and solitary fibrous tumor, may be considered. Primary sarcomas of the prostate such as leiomyosarcoma may be a consideration but, in contrast to phyllodes tumor, are a monophasic tumor [17]. The latter may occur as a dominant pattern in a sarcomatous transformation of a phyllodes tumor [6]. Carcinosarcoma or sarcomatoid carcinoma are possible considerations when an overtly malignant spindle cell component is present, but, unlike phyllodes tumor, they have a malignant epithelial component or evidence of epithelial differentiation in the neoplastic spindle cells [18, 19]. Stromal tumors of uncertain malignant potential (STUMP) [20-22] is a recently introduced term intended to provide a unifying classification for stromal tumors of the prostate , including phyllodes tumor, that are not overt sarcomas. There remains some controversy regarding definition, and it is not clear that this term refers to a group of lesions that share a common pathogenesis or biology. The term most often refers to a pattern of atypical, degenerative appearing, stromal cells distributed diffusely, with variable cellularity, amongst benign glands [21, 22], with an appearance of diffuse prostatic stromal hyperplasia with bizarre nuclei, but with the potential to recur [21, 22]. Three additional patterns are described. They are, in order of decreasing reported frequency; i) hypercellular stroma in a gland-stromal nodule, without cytologic atypia or mitoses, resembling benign prostatic hyperplasia (BPH), ii) extensive overgrowth of bland, mitotically inactive stromal cells with myxoid stroma, resembling the stromal nodules of BPH, but lacking discrete nodularity, iii) phyllodes-type growth. This diverse group appears to have in common the risk of being associated with sarcoma, suggesting that any of these lesion may undergo sarcomatous transformation, albeit rarely, necessitating thorough and cautious evaluation whenever any of these patterns is encountered. Phyllodes tumor is a distinct biphasic lesion that can be separately identified from the other stromal lesions [6]. Its clinicopathological features are more in keeping with a neoplasm than an "atypical hyperplasia". There is genetic evidence for different clonal origins of the stromal and epithelial components [29]. Although a benign clinical course has been emphasized in some reports [3, 4], accumulated experience in the literature indicates that many of these patients develop local recurrence [1, 2, 6, 9, 10]. Rarely, tumors with overtly malignant stroma have given rise to distant lung, bone and abdominal wall sarcomatous metastases [6, 9, 10]. Lymph node metastases have not been observed. Additional prognostic information may be provided by subdivision of these tumor into low and high-grade groups. Of note, however, as in the submitted case, even low-grade tumors may recur [6]. 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