Case 11 -

Diagnosis and Understanding the Significance of HGPIN, Atypical Small Acinar Proliferation (ASAP) And Recognition of Morphological Features of Cancer Following Therapy (continued) Rajal Shah and Ming Zhou

Case 11: A 60 year-old man had rising PSA 2 years after brachytherapy for Gleason 3+3=6 prostate cancer. He underwent a 12-core prostate biopsy. Diagnosis: Residual adenocarcinoma of the prostate with radiation treatment effect. Histological Changes in Benign and Malignant Prostate Tissue Following Treatment Hormonal deprivation therapy Prostate is an androgen-responsive organ and androgen pathway plays a critical role in the development and function of prostate gland, as well as pathogenesis of benign and malignant diseases. Androgen pathway involves several key molecules and enzymes, including leutinizing hormone release hormone (LHRH), 5-alpha-reductase, testosterone, and androgen receptors. These molecules are the targets of hormonal ablation therapy. Finasteride (Proscar) inhibits 5-alpha-reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT), therefore reduces the production of DHT, a more potent form of androgens. This drug is used in the treatment of benign prostatic hyperplasia, and more recently in prostate cancer chemoprevention. However, this drug does not produce significant effect on benign and malignant prostate tissue [1, 2]. On the other hand, LHRH analogs (Lupron, Zoladex) and anti-androgens (Flutamide, and Casodex) can be used singly or in combination (total androgen blockade) in treatment of advanced stage prostate cancer. This latter modality, termed medical castration, may result in significant histological changes in both benign and malignant prostate tissues [1, 3, 4, 5]. Benign tissue, following hormonal ablation, exhibits glandular atrophy and stromal predominance. Basal cells are prominent with diffused basal cell hyperplasia. Atrophic prostatic glands can also undergo diffuse squamous and transitional cell metaplasia. Marked squamous metaplasia, a characteristic feature seen in patients on estrogen therapy, is rarely encountered in present day anti-androgen therapy. Stroma can become edematous, fibrotic and have abundant inflammatory infiltrates. Hormonal ablation may result in three histological patterns in prostate cancer. The cancer glands may become atrophic with pyknotic and hyperchromatic nuclei. These glands may be indistinguishable from benign atrophic glands. Only their crowded infiltrative nature is diagnostic of prostate cancer. The second pattern is that cancer cells develop pyknotic nuclei and abundant xanthomatous cytoplasm, resembling histiocytes. However, the presence of cancer cells with less or no hormonal induced changes help establish a cancer diagnosis. The third pattern is pools of mucin with individual cancer cells floating in it when cancer cells dissolve. The diagnosis of prostate cancer with marked hormonal induced changes is often difficult and requires immunohistochemical studies. Cancer cells will remain positive for pancytokeratin and negative for basal cell markers. They may be also positive for AMACR, PSA and PSAP, although the expression of these markers may be markedly reduced after hormonal therapy [6, 7, 8]. Radiation therapy Radiation therapy, including external being and seed implantation (brachytherapy) are used to treat clinically localized or locally advanced prostate cancer. Brachytherapy has become popular in recent years. It is still controversial whether it is necessary to perform needle biopsy to document histological presence of cancer for rising PSA following radiation therapy. However it is generally agreed upon that a biopsy should be performed in order to distinguish local recurrence from distant metastases and to have a histological confirmation before a salvage prostatectomy. Often pathologists do not get a history of prior radiation therapy; therefore it is important to recognize the histological features of radiation atypia to avoid misdiagnosis of cancer. Radiation may result in significant changes in both benign and malignant prostate tissue [9]. In benign prostate tissue, it causes glandular atrophy and stromal predominance. Benign glands will still maintain their lobular architecture. Each individual gland will have multi-layering of cells with scattered marked atypical cells. On the other hand, Irradiated cancer cells form small nests of single cells with abundant xanthomatous cytoplasm and pyknotic nuclei. Cancer cells may not be affected by radiation to the same degree. Some may be less affected and resembles ordinary prostate cancer. Although mainly performed to document local and residual disease, post-radiation biopsy can also provide some prognostic information [10]. The biopsy should be performed 30 to 36 months following radiation therapy, as dying cancer cells may persist up to 30 months after radiation therapy. A post-radiation biopsy could show three findings: positive for cancer, negative for cancer and positive for cancer with treatment effect. Patients with negative biopsies have better prognosis than patients with biopsies with cancer cells showing treatment effect. The worst prognosis is seen in patients with biopsies showing cancer cells unaffected by radiation. In patients with post-radiation biopsies showing cancer cells with treatment effect, 30% will have no evidence of cancer, 34% will have residual cancer, and 36% will demonstrate local and distant failure in subsequent biopsies. . When pathologists are suspecting hormonal or radiation therapy, he should obtain clinical history to confirm the histological impression. Gleason grading should not be applied to the cases with pronounced treatment effect. However, it may be performed in cases with no treatment effect. The degree of treatment effect is usually not graded or reported [11]. References: Rubin, M.A., et al., Effects of long-term finasteride treatment on prostate cancer morphology and clinical outcome. Urology, 2005. 66(5): p. 930-4. Yang, X.J., et al., Does long-term finasteride therapy affect the histologic features of benign prostatic tissue and prostate cancer on needle biopsy? PLESS Study Group. Proscar Long-Term Efficacy and Safety Study. Urology, 1999. 53(4): p. 696-700. Tetu, B., et al., Effect of combination endocrine therapy (LHRH agonist and flutamide) on normal prostate and prostatic adenocarcinoma. A histopathologic and immunohistochemical study. Am J Surg Pathol, 1991. 15(2): p. 111-20. Armas, O.A., et al., Clinical and pathobiological effects of neoadjuvant total androgen ablation therapy on clinically localized prostatic adenocarcinoma. Am J Surg Pathol, 1994. 18(10): p. 979-91. Vailancourt, L., et al., Effect of neoadjuvant endocrine therapy (combined androgen blockade) on normal prostate and prostatic carcinoma. A randomized study. Am J Surg Pathol, 1996. 20(1): p. 86-93. Vernon, S.E. and W.D. Williams, Pre-treatment and post-treatment evaluation of prostatic adenocarcinoma for prostatic specific acid phosphatase and prostatic specific antigen by immunohistochemistry. J Urol, 1983. 130(1): p. 95-8. Grignon, D. and M. Troster, Changes in immunohistochemical staining in prostatic adenocarcinoma following diethylstilbestrol therapy. Prostate, 1985. 7(2): p. 195-202. Kuefer, R., et al., alpha-Methylacyl-CoA racemase: expression levels of this novel cancer biomarker depend on tumor differentiation. Am J Pathol, 2002. 161(3): p. 841-8. Bostwick, D.G., B.M. Egbert, and L.F. Fajardo, Radiation injury of the normal and neoplastic prostate. Am J Surg Pathol, 1982. 6(6): p. 541-51. Crook, J., et al., Postradiotherapy prostate biopsies: what do they really mean? Results for 498 patients. Int J Radiat Oncol Biol Phys, 2000. 48(2): p. 355-67. Amin, M., et al., Prognostic and predictive factors and reporting of prostate carcinoma in prostate needle biopsy specimens. Scand J Urol Nephrol Suppl, 2005(216): p. 20-33.