Interpretation of Prostate Needle Biopsies
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
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.
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
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
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
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
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 . 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 . 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 .
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