Prostatic stromal hyperplasia with atypia (PSHA) is a

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1 Prostatic Stromal Hyperplasia With Atypia Follow-up Study of 18 Cases Deloar Hossain, MD, FRCPC; Isabelle Meiers, MD; Junqi Qian, MD; Gregory T. MacLennan, MD; David G. Bostwick, MD, MBA Context. Prostatic stromal hyperplasia with atypia is a rare lesion that can be mistaken for sarcoma because of the presence of atypical, bizarre, degenerative myocyte nuclei. Objective. To determine the diagnostic criteria and clinical significance of prostatic stromal hyperplasia with atypia. Design. Eighteen cases of prostatic stromal hyperplasia with atypia were reviewed from the consultation file of one of the authors (D.G.B.). Results. Prostatic stromal hyperplasia with atypia consists of 1 or more ill-defined, uncircumscribed, hyperplastic stromal nodules, with variable numbers of atypical, bizarre giant cells, with vacuolated nuclei, smudged chromatin, and frequent multinucleation infiltrating around benign acini. There was a hypocellular, loose, myxoid stromal matrix, with ectatic hyalinized vessels and mild to moderate chronic inflammation. Stromal cells displayed intense immunoreactivity for androgen receptors and vimentin, but moderate reactivity for desmin and actin. There were 3 local recurrences, with a mean follow-up of 6.3 years (range, years), but none developed evidence of sarcomatous transformation or malignancy. Conclusions. Prostatic stromal hyperplasia with atypia is a rare, benign lesion, composed of degenerative myocytes with atypia that is histologically and clinically reminiscent of benign counterparts in the myometrium, breast, vulva, vagina, and elsewhere. Recognition of this distinctive entity should allow separation from phyllodes tumor and sarcoma of the prostate. The phrase stromal tumor of uncertain malignant potential is inappropriate for this benign tumor, and its use is discouraged. (Arch Pathol Lab Med. 2008;132: ) Prostatic stromal hyperplasia with atypia (PSHA) is a rare lesion that can be mistaken for sarcoma because of the presence of bizarre, degenerative myocyte nuclei The nuclear abnormalities are identical to those of symplastic leiomyoma of the myometrium, raising concern about sarcoma, particularly in limited samples, such as needle biopsies. The diagnostic criteria and clinical significance of this lesion are not well established, and features that separate this lesion from sarcoma are not fully defined. Previously, we reported 6 11 cases of this unusual, soft tissue lesion of the prostate, with a mean follow-up of 2.9 years. That study included 7 other cases of prostatic leiomyoma with atypia (reported initially as stromal hyperplasia with atypia, leiomyoma-like pattern) that are excluded from the present study; those cases and other related cases represent symplastic leiomyoma (leiomyoma with atypical cells) and are presented in a separate Accepted for publication May 8, From the Bostwick Laboratories, Glen Allen, Va (Drs Hossain, Meiers, Qian, and Bostwick); and the Department of Pathology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Pathology and Laboratory Medicine Service, Cleveland, Ohio (Dr MacLennan). The authors have no relevant financial interest in the products or companies described in this article. Reprints: David G. Bostwick, MD, MBA, Bostwick Laboratories, 4355 Innslake Dr, Glen Allen, VA ( bostwick@ bostwicklaboratories.com). study. 11 The current report expands our initial series to 18 cases and includes longer mean follow-up (6.3 years). Our findings underscore the apparent benign nature of PSHA. MATERIALS AND METHODS We identified 18 cases of PSHA seen in consultation between 1981 and 2006 by one of the authors (D.G.B.). All hematoxylineosin stained sections were available in each case, as was a toluidine blue stained slide from 2 cases. Clinical information and follow-up were obtained from the medical records and referring physicians in all cases. Immunohistochemical stains were performed in 10 cases. Fourmicrometer sections were prepared from formalin-fixed, paraffinembedded tissue samples. Immunohistochemical staining was performed on the Ventana ES (Tucson, Ariz) autostainer using the avidin-biotin method. All immunohistochemical staining was carried out after microwave-mediated antigen retrieval. Antibodies used are as follows: -smooth muscle actin (DAKO, Carpinteria, Calif; 1:100 dilution), vimentin (DAKO; 1:100), desmin (DAKO; 1:100), estrogen receptors (DAKO; 1:100), progesterone receptors (DAKO; 1:100), androgen receptors (DAKO; 1:00), and Ki-67 (DAKO; 1:100). Staining was evaluated as a percentage of positive cells in 10% increments (0% 100%). Immunohistochemical stain was evaluated jointly by 3 pathologists (D.H., J.Q., and D.G.B.). Appropriate negative and positive controls were run in parallel with each batch of immunostains. Immunostaining was considered positive if the intensity of staining was equal to or greater than the intensity of the positive controls (moderate or strong staining). Arch Pathol Lab Med Vol 132, November 2008 Prostatic Stromal Hyperplasia With Atypia Hossain et al 1729

2 Table 1. Case No. Age, y Clinical Presentation Prostatic Stromal Hyperplasia With Atypia: Clinical and Pathologic Findings* Diagnostic Specimen Initial Treatment Persistence/ Recurrence Recent Status Follow-up, y 1 71 Urinary obstruction Needle biopsy None Yes BPH Urinary obstruction and hematuria Needle biopsy None Yes BPH Elevated PSA Needle biopsy None Yes BPH Urinary obstruction TURP (8 g) None None NED Urinary obstruction TURP (19 g) TURP None NED Urinary obstruction Needle biopsy None None DOC Urinary obstruction TURP None None DOC Urinary obstruction Needle biopsy None None BPH Urinary obstruction and hematuria Prostatectomy Simple prostatectomy None NED Urinary obstruction TURP (150 g) TURP None DOC Elevated PSA Prostatectomy Radical prostatectomy None NED Elevated PSA Needle biopsy None None BPH Urinary obstruction Needle biopsy None None BPH Abnormal DRE Needle biopsy None None BPH Abnormal DRE Needle biopsy None None NED Elevated PSA Needle biopsy None None NED Elevated PSA Needle biopsy None None NED Abnormal DRE Needle biopsy None None NED 0.5 * BPH indicates symptomatic benign prostatic hyperplasia; PSA, prostate specific antigen; TURP, transurethral resection of prostate; NED, no evidence of disease; DOC, death due to other cause; and DRE, digital rectal examination. Three cases of residual or recurrent prostatic stromal hyperplasia with atypia in subsequent repeat needle core biopsies. Case associated with adenocarcinoma. RESULTS Clinical and Pathologic Findings We identified 18 cases of PSHA present in 12 needle biopsies, 4 transurethral resections (specimens weighing g), and 2 retropubic prostatectomies (Table 1). Patients ranged in age from 46 to 80 years old (mean, 64 years). Ten patients presented with urinary obstructive symptoms and underwent needle biopsy, transurethral resection, or open, simple prostatectomy (adenomectomy). In 3 patients, PSHA was discovered in needle biopsies performed for abnormal findings from digital rectal examination; in 5 patients, PSHA was noted in needle biopsies performed for elevated serum prostate specific antigen concentration; and in 1 patient, PSHA was discovered incidentally in a radical prostatectomy specimen performed for treatment of adenocarcinoma. The transurethral resection and biopsy specimens invariably consisted predominantly of typical nodular hyperplasia, with only a minor component ( 20% of the lesion) of PSHA. In the simple prostatectomy, PSHA comprised only a minor ( 5% of the lesion) component. Prostatic stromal hyperplasia with atypia in the radical prostatectomy was contralateral to the adenocarcinoma and also comprised a minor component ( 5% of the lesion). No coexistent sarcoma was present in any of the primary or recurrent cases. Prostatic stromal hyperplasia with atypia consisted of one or more uncircumscribed, ill-defined, hyperplastic stromal nodules with atypical cells infiltrating diffusely around hyperplastic acini; there were no apparent abnormalities of the epithelium (Figure 1, A). The histologic hallmark of PSHA was the presence of atypical cells with distinctive nuclear features, including variable numbers of large, bizarre giant cells, with vacuolated nuclei, smudged chromatin, inconspicuous nucleoli, and frequent multinucleation (Figure 1, B). Most of these cells contained a moderate amount of eosinophilic cytoplasm with indistinct cell borders. No mitotic figures were observed in any case. The atypical cells were embedded in a loose hypocellular myxoid matrix (Figure 1, C). The cellularity was uniform, and the arrangement of the atypical cells was typically haphazard. There were invariably large ectatic vessels, with hyalinized, thick walls, accompanied by a variable number of lymphocytes, plasma cells, and rare mast cells (Figure 1, D). Immunohistochemical Studies Immunohistochemical studies were performed in 10 cases in which tissue was available for evaluation (Table 2), including 1 tissue block from 9 cases and 2 tissue blocks from 1 recurrent case. The atypical stromal cells displayed intense immunoreactivity for vimentin (Figure 2, A) and androgen receptors (Figure 2, B), moderate reactivity for desmin and actin, variable reactivity for progesterone receptors, and no reactivity for estrogen receptors or Ki-67 (Table 2). Patient Follow-up Studies Clinical follow-up was available in all cases, with a mean follow-up of 6.3 years (range, years). Eight patients had symptomatic, benign prostatic hyperplasia, 7 were asymptomatic, and 3 patients died of diseases with unrelated causes. Residual or recurrent PSHA (Table 1) was seen in 3 (17%) of 18 patients. Residual or recurrent PSHA was present in tissue from the same side, diagnosed in subsequent, site-directed, sextant needle core biopsies (Table 1). The interval between the initial and follow-up biopsies for residual or recurrent cases was 1, 1.5, and 3 years. The histologic findings in tissue from residual or recurrent PSHA were identical to those seen in the original specimen. No evidence of stromal overgrowth or sarcomatous transformation was noted in any case. COMMENT Prostatic stromal hyperplasia with atypia is a rare lesion that has been referred to by a variety of terms, including atypical stromal hyperplasia, stromal hyperplasia with bizarre nuclei, symplastic leiomyoma, Pseudosarcomatous 1730 Arch Pathol Lab Med Vol 132, November 2008 Prostatic Stromal Hyperplasia With Atypia Hossain et al

3 Figure 1. Prostatic stromal hyperplasia with atypia (A) showing atypical cells in the stroma and around the benign acini, (B) showing typical cells with degenerative smudge chromatin, (C) with myxoid stroma and scattered atypical cells, and (D) with ectatic hyalinized blood vessel (hematoxylin-eosin, original magnifications 100 [A], 400 [B], and 200 [C and D]). Figure 2. Immunoreactivity in prostatic stromal hyperplasia with atypia (PSHA). Strong cytoplasmic immunoreactivity of stromal cells to vimentin (A) and strong nuclear immunoreactivity for androgen receptors (B) (original magnifications 400). Arch Pathol Lab Med Vol 132, November 2008 Prostatic Stromal Hyperplasia With Atypia Hossain et al 1731

4 Table 2. Prostatic Stromal Hyperplasia With Atypia: Immunohistochemical Findings in 10 Cases* Case No. Ki-67 Desmin Actin Vimentin Estrogen Progesterone Androgen * Staining was evaluated as a percentage of cells positive in 10% increments (0% 100%). Two specimens from this case with identical histology and immunohistochemical features. lesion, pseudoneoplastic lesion of the prostate gland, prostate stromal proliferation of unknown malignant potential, and prostatic stromal tumor of uncertain malignant potential We prefer the term PSHA because it expresses the benign nature of the lesion as evidenced by our followup study. In our series, patients ranged in age from 46 to 80 years (mean, 64 years) and underwent procedures related to typical lower urinary tract obstructive symptoms, abnormal digital rectal examination, or elevated serum prostate-specific antigen. Prostatic stromal hyperplasia with atypia is characterized by the presence of bizarre giant cells with vacuolated nuclei and frequent multinucleation. The chromatin is smudged rather than hyperchromatic. Nucleoli are inconspicuous or absent owing in part to the nuclear smudging. Despite exhibiting cytologic features that are worrisome for malignancy, PSHA does not have mitotic figures or necrosis. We interpret these atypical features to be reactive and degenerative, rather than neoplastic, changes, similar to the findings in reactive stromal cells in lesions from various sites, such as the cervix, vagina, vulva, bladder, and breast. 12 The atypical cells in PSHA displayed consistent and intense nuclear immunoreactivity for androgen receptors, variable reactivity for progesterone receptors, and no reactivity for estrogen receptors and Ki-67. This suggests that this lesion results from local hypersensitivity to androgen, with upregulation of androgen receptors in these cells. This pattern of expression in PSHA is similar to the expression profile in benign prostatic hyperplasia, except for the lack of expression of estrogen receptors. 13 Others have suggested that the reactive stromal cells result from an ill-defined mast cell interaction, 12 but we found little or no inflammation and no noticeable increase in the number of mast cells. Radiotherapy may also induce atypia in stromal cells, 14 but cannot be held accountable for the findings in our cases because there was no history of radiation. The differential diagnosis of PSHA includes prostatic leiomyoma with atypical cells, phyllodes tumor, leiomyosarcoma, and other sarcomas. Prostatic stromal hyperplasia with atypia is separated from prostatic leiomyoma with atypical cells by differing histologic and immunohistochemical findings. 15 Atypical cells in the PSHA infiltrate around benign prostatic acini, whereas leiomyoma with atypical cells (symplastic leiomyoma) consists of a solid expansile growth pattern with atypical cells distributed haphazardly within the nodule. The atypical stromal cells in the PSHA displayed intense immunoreactivity for vimentin but only moderate reactivity for desmin and actin. Conversely, the cells in the prostatic leiomyoma with atypia displayed intense cytoplasmic immunoreactivity for desmin and actin, and only weak to moderate reactivity for vimentin. Phyllodes tumor of the prostate is characterized by a biphasic growth pattern with variably cellular stroma intimately associated with compressed, elongated glands that often have a leaflike configuration. 16 Although it is frequently difficult to appreciate in needle biopsies, the cellular stroma of phyllodes tumor often displays cytologic atypia and has increased mitotic activity. Leiomyosarcoma of the prostate is uncommon and is usually large and nodular, exhibiting cytologic atypia, high mitotic activity, and occasional foci of coagulative necrosis. These features differ from the vacuolated nuclei, smudged chromatin, and lack of mitotic figures and necrosis in PSHA. These features may also be used to separate PSHA from other rare sarcomas of the prostate. Nonetheless, in some cases with limited amounts of tissue available for examination, this distinction may be difficult. Prostate stromal hyperplasia with atypia is a benign finding associated with infrequent recurrence, similar to and usually coexisting with typical nodular hyperplasia; it lacks evidence of stromal overgrowth or malignant transformation with follow-up. Some previous authors have lumped this distinctive entity with phyllodes tumor (a tumor with definite malignant potential) and low-grade sarcoma, using the phrase stromal tumor of uncertain malignant potential, thereby erroneously implying that this lesion is associated with an unpredictable outcome. 3,17 The reported data support our finding that PSHA is a benign condition; thus, we believe PSHA is the preferable terminology. We discourage use of the terms prostatic stromal proliferation of uncertain malignant potential or stromal tumor of uncertain malignant potential, similar to our previous recommendation. 18 In summary, PSHA is a reactive and/or degenerative process that occurs in a histologically distinct pattern associated with typical nodular hyperplasia. Stromal hyperplasia with atypia is benign and rarely recurs. Recognition of this benign entity and its distinction from other neoplastic lesions of the prostate has important therapeutic and prognostic implications. References 1. Attah EB, Powell ME. Atypical stromal hyperplasia of the prostate gland. Am J Clin Pathol. 1977;67: Eble JN, Tejada E. Prostatic stromal hyperplasia with bizarre nuclei. Arch Pathol Lab Med. 1991;115: Gaudin PB, Rosai J, Epstein JI. Sarcomas and related proliferative lesions of specialized prostatic stroma: a clinicopathologic study of 22 cases. 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