There is no significant difference in the histologic appearance of irradiated benign glands when the patients are treated with androgen deprivation therapy Gaudin et al. The surrounding stromal cells also undergo chronic inflammatory processes.
The molecular and cellular mechanisms underlying this chronic inflammatory change are well described. Briefly, after the initial insult of radiation therapy, a cascade of inflammatory mediators is initiated including TNF-alpha, interleukin-1, and interleukin-6 Haase ; Bentzen Other components include simple sugars, amino acids, ascorbic acids, and prostaglandins. In general, radiation changes are similar in patients receiving external beam radiation and brachytherapy, although the brachytherapy-associated changes may be more marked Magi-Galluzzi et al.
Early histologic changes in the irradiated prostate, seen after several weeks, include nuclear contraction, signs of cytoplasmic injury, and small areas of early necrosis. These areas of injury and necrosis initiate the well described processes of acute inflammation, where polymorphonuclear cells, macrophages, and lymphocytes are recruited in a characteristic chronological pattern. As treatment progresses, a mixed acute-late inflammatory histology appearance predominates that gradually gives way to fibrotic change once radiation treatment has been completed.
Recruitment of cells typically involved in the chronic inflammatory process is also evident. Specifically, macrophages are seen in the early phase of fibrosis, which chemically recruit fibroblasts, which in turn transform to fibrocytes.
Additionally, vascular changes are noted, including endothelial cell damage, intimal hyperplasia, marked arterial luminal narrowing, arterial medial thickening, cytoplasmic swelling, hyaloid changes of the capillary wall, and thinning of the capillary network Sheaff and Baithun ; Herrmann Prostate cancer cells respond differently than benign prostate cells after radiation therapy has been administered. This response, although characteristic, is quite variable, ranging from significant treatment-related changes to no apparent change after radiation therapy Gaudin et al.
Prostate cancer cells with no evident effect had an appearance similar to pre-treatment specimens. Prostate cancers with profound radiation changes demonstrated several characteristic morphologic changes including a decrease in the number of neoplastic glands, with residual glands in a more irregular morphology and some individual scattered cells not associated with glands. The cells demonstrated abundant cytoplasm with vacuolated and reticulated changes but little nuclear pleomorphism.
In contrast to radiation changes in benign prostate tissues, radiation changes in prostate cancer cells were not associated with nuclear pleomorphism or prominent nucleoli.
Furthermore, benign glands with radiation changes were extremely reactive to immunohistochemical stains for cytokeratin 34[beta]E12 and had a variable staining pattern to antibodies specific for prostate-specific antigen PSA , while cancerous glands with radiation changes were not reactive to cytokeratin 34[beta]E12 were intensely immunoreactive for PSA. Additionally, while benign glands tended to maintain a lobular architecture, cancerous areas are arranged in a random, infiltrative morphology.
Part of the issue in determining the effects of irradiation of the prostate gland is the presence of a prostate cancer, which is the most common reason to treat the gland.
Initially, following 60—70 Gy doses, necrosis of the cancer cells occur. Months to years later, the glandular epithelium are reduced in size and becomes atrophic and are replaced by fibrosis. Vascular changes are quite severe with obliteration of arterioles with internal forming cells.
Despite these characteristic changes, histopathologic interpretation of biopsies of a patient treated with radiation therapy is fraught with difficulty Bostwick The risk of misinterpretation is that benign radiation changes will be mistaken for prostate cancer. In general, rebiopsy after radiation treatment Fig. The presence of malignant cells in the biopsy specimen after radiation therapy should not be automatically interpreted as treatment failure.
Prostate cancer cell death is a post mitotic event in a cancer with a long potential doubling time, meaning that regression of viable cancer is evident to at least 3 years after treatment Crook et al. Prestidge et al.
In general, if radiation biopsies show profound treatment effect in the adenocarcinoma, these patients are unlikely to fail therapy. No resudial epithelium can be recognized. The remaining, nonneoplastic glands show atrophy and extensive squamous metaplasa.
There are also histological changes from the use of androgen deprivation therapy alone. Androgen stimulation is an important component of normal prostate metabolism. In the prostate gland, testosterone is converted into dihydrotestosterone by alphareductase. Dihydrotestosterone stimulates growth of both normal prostate tissue and prostate adenocarcinoma cells. When androgen deprivation is administered, consistent effects can be seen regardless if combined androgen blockade LHRH agonist and peripheral androgen receptor blocker or anti-androgen monotherapy LHRH agonist alone is used.
Degenerative phenotypes are noted, including nuclear pyknosis, and vacuolization of the cytoplasm Tetu ; Armas Furthermore, androgen deprivation also suppresses the histological changes commonly used to diagnose adenocarcinoma, such as increased nuclear size, nuclear pleomorphism, and prominent nucleoli. Therefore, care must be taken in the histological evaluation of patients who have received androgen deprivation therapy prior to prostate biopsy because there is a risk of underestimating both tumor extent and Gleason score.
Rigorous examination of the specimen for scant individual malignant cells and special immunohistochemical stains are essential in this clinical situation Vernon In addition to the above commonly used strategies of androgen blockade, other agents, such as estrogens and 5-alpha reductase inhibitors also cause histological changes in normal and malignant prostate cells. The effect of estrogen administration on prostate histology is mainly of historical interest, as estrogens are not commonly used in contemporary treatment algorithms.
However, estrogens induce the above changes seen with modern anti-androgen regimens and further cause a unique effect of squamous metaplasia in benign and malignant prostate cells Schenken ; Franks Finasteride and dutasteride block the conversion of testosterone to dihydrotestosterone in the prostate gland by inhibiting 5-alpha reductase and are used in a variety of clinical situations including BPH and androgenetic alopecia.
Their use has been found to have minimal influence on prostate cancer cells and does not typically interfere with pathologic diagnosis or the prognosis of Gleason grade Yang et al. Furthermore, 5-alpha reductase inhibitors do appear to have the ability to affect the incidence and grade of prostate cancers in men who use them Andrioleet al.
The most compelling argument for this comes from the Prostate Cancer Prevention Trial, which demonstrated that healthy men treated with 5-alpha-reductase inhibitors had a The normal complex arborizing glands are reduced to narrow cavities with a few branches embedded in dense collagen scoring. Radiation also causes changes in the urothelium Antonakopoulos et al. Irradiated urothelial cells demonstrate changes including nuclear pleomorphism, swollen cytoplasm, and altered labeling indices as compared to non-irradiated urothelial cells.
Loss of tight junctions is noted, allowing hypertonic urine access to the interstitial area, leading to chemical fibrotic injury and increasing the probability of bacterial infection and subsequent inflammatory damage. These morphological changes correlate clinically with the onset of irritative urinary symptoms encountered after a course of radiation therapy Marks et al. When bulbomembranous urethral strictures are examined histologically, there is an initial ulceration of the urothelium that develops into proliferative changes of stratified squamous epithelium with interposed elongated myofibroblasts and multinucleated giant cells that produce abundant collagen Baskin et al.
The myofibroblasts are thought to be a primary causative factor for stricture formation. The ubiquitous stromal changes of radiation therapy are also noted, including obliterative endarteritis, ischemia, and fibrosis. In laboratory rats after single fraction doses of 1, and 2, cGy, after 5 months, the animals had impaired responses to central and peripheral stimulation, at both doses, increased with the higher dose; the number of nerve fibers positive for nitric oxide synthase.
The mechanism for radiation-induced erectile dysfunction was attributed to defective vascularity of penile tissues as well as peroneal nerves and smooth muscle. Acute toxicities are attributable to effects from acute inflammation, while late toxicities are usually attributable to radiation-induced fibrosis, vascular damage, and altered patterns of vasculature.
Late effects of radiation are particularly multifactorial, being affected by comorbidities, genetic factors, and other cancer treatments in addition to radiation-related variables such as total dose, dose per fraction, fractionation schedule, and dose—volume parameters.
With modern teletherapy techniques such as intensity modulated radiation therapy IMRT and image-guided radiation therapy IGRT , in addition to improvements in brachytherapy, the overall morbidity of external beam radiation therapy has been significantly reduced despite higher contemporary prescription doses. The addition of systemic agents, such as cytotoxic chemotherapy or androgen deprivation therapy, may alter the risk of these toxicities Zelefsky et al.
The process of tumescence is a complex process, depending on afferent cavernous nerves supplying the penis with nitric oxide. Relaxation of the afferent internal pudendal and accessory pudendal arterioles and cavernosal smooth muscle occurs, which allows for filling of the trabecular space.
Increased venous resistance prevents outflow, causing trapping of blood, and contraction of the bulbocavernosus and bulbospongiosus muscles further increase intratrabecular space pressure. In general, radiation-induced impotence is thought to manifest within the first 2 years after treatment van der Wielen The decline in ability to obtain and maintain erections after therapy has historically been thought to be caused by radiation exposure of tissues involved in the process of tumescence, including the afferent neurovascular bundles, the penile bulb, and the corpora cavernosa Fisch et al.
However, a recent publication has demonstrated that radiation-induced erectile dysfunction is mainly due to afferent arterial insufficiency, with only a small percentage of cases due to changes in veno-occlusive capacity Zelefsky and Eid Additionally, several publications suggest that doses to structures such as the penile bulb are not predictive of post-therapy impotence van der Wielen et al.
Regardless, modern radiation techniques are able to minimize radiation dose to these tissues that are at risk, including the penile bulb and base of the penis, possibly decreasing the rates of radiation-related erectile dysfunction Sethi et al. However, sparing the neurovascular bundle with external beam techniques is not yet achievable, given its close proximity to the prostate, need for the appropriate PTV margins to account for interfraction and intrafraction motion, and continuing trends of dose escalation.
Additionally, a multitude of other factors can exacerbate post-treatment erectile dysfunction, including existing peripheral vascular disease, diabetes mellitus, smoking history, hypertension, hypercholesterolemia, administration of androgen deprivation therapy, and other medications Hollenbeck et al.
The social situation of the patient also has a significant role on sexual function, including the presence or absence of a willing partner and the physiological and emotional impact of cancer diagnosis and treatment on the patient Goldstein et al. Furthermore, independent of a diagnosis of cancer, loss of erectile function is common in men between and years old, with up to 26 out of every 1, men developing ED each year Johannes et al.
It is therefore difficult, if not impossible, to define the radiation parameters clearly causing sexual dysfunction and the time frame in which they manifest after treatment.
It is important that the evaluation of ED is performed with a detailed history including sexual, medical, and psychosocial status and other laboratory tests Rosen et al.
However, some relevant radiation-specific literature is available on this topic and merits discussion Crook et al. After interstitial penile brachytherapy, moist desquamation appears to be the only significant acute toxicity, peaking 2—3 weeks after treatment and taking several months to heal. Patients are also at risk for acute post-treatment adhesions which usually present with a split or deviated urine flow from the meatus. Soft tissue necrosis usually appears as an area of progressive ulceration that typically takes place 6—18 months after brachytherapy Delannes et al.
Ulcerations leading to necrosis can be exacerbated by thermal injury or traumatic episodes to the penis, including biopsy. Radiation-induced penile urethral strictures occur between 1 and 3 years after treatment and can present with altered urodynamics, divergent stream, pain, or hematuria. The skin can also undergo chronic atrophic change after treatment, including thinning of the dermis and epidermis, formation of irregular pigmentation patterns with gain or loss of natural pigment, increased skin sensitivity or pain, and formation of teleangectatic vessels.
Benign prostatic hyperplasia. Hyperplasia comprises of both glandular white asterisk and stromal black asterisk elements. AFS: anterior fibromuscular stroma; white arrows: neurovascular bundles which are surrounded by fat; R: rectum with endorectal coil. Table 1. Table summarizing the histologic composition and embryologic origins of the various zones of the prostate gland.
Figure 5. Seminal vesicles. Seminal vesicles are high signal-intensity fluid-filled pouches with a low signal-intensity wall, arranged in a grapelike pattern.
White arrowheads: prostate-seminal vesicle angle; PB: penile bulb; L: levator ani; black arrowheads: external urethral sphincter; PZ: peripheral zone. BL: bladder; R: rectum with endorectal coil. Figure 6. Note the normal-appearing contralateral peripheral zone PZ comprised of glandular elements. Also, the right rectoprostatic angle appears slightly ill-defined, although no definite bulge is seen. This would comprise N1 disease, which would fall under Stage IV category.
Figure 7. Prostate cancer. Axial T2WI showing a right anterior transitional zone tumor within the midgland, likely also involving a portion of the anterior fibromuscular stroma. Notice that the tumor creates a slight anterior bulge arrowheads.
Figure 8. Notice the subtle asymmetric posterolateral bulging along the left rectoprostatic angle which would be concerning for possible extracapsular extension arrowheads.
Again notice the subtle asymmetric posterolateral bulging which would be concerning for possible extracapsular extension arrowheads. Figure 9. Prostate cancer with seminal vesicle invasion. B: bladder; SV: normal-appearing seminal vesicle tubules. B: bladder.
Table 2. Table 3. References M. Ketchandji, Y. Kuo, V. Shahinian, and J. Barentsz, J. Richenberg, R. Clements et al. Wang, Y. Mazaheri, J. Zhang, N. Ishill, K. Kuroiwa, and H. Hricak and P. Scardino, Prostate Cancer. Wilson, J.
Griffen, M. Leshin, and F. View at: Google Scholar J. Imperato McGinley, L. Guerrero, and T. View at: Google Scholar C. Lee, O. Akin-Olugbade, and A. Janus and M. View at: Google Scholar G. Villeirs, K. Verstraete, W. Ayala, J. Ro, R. Babaian et al. View at: Google Scholar R. Myers, D. Cahill, R. Devine, and B. Lepor, M.
Gregerman, R. Crosby, F. Mostofi, and P. View at: Google Scholar M. Llanes, J. Angulo, and A. Walsh, H. Lepor, and J. When the semen regains its fluid state, sperm can then pass farther into the female reproductive tract. The prostate normally doubles in size during puberty. At approximately age 25, it gradually begins to enlarge again.
This enlargement does not usually cause problems; however, abnormal growth of the prostate, or benign prostatic hyperplasia BPH , can cause constriction of the urethra as it passes through the middle of the prostate gland, leading to a number of lower urinary tract symptoms such as a frequent and intense urge to urinate, a weak stream, and a sensation that the bladder has not emptied completely.
By age 60, approximately 40 percent of men have some degree of BPH. By age 80, the number of affected individuals has jumped to as many as 80 percent. Treatments for BPH attempt to relieve the pressure on the urethra so that urine can flow more normally.
Mild to moderate symptoms are treated with medication; whereas, severe enlargement of the prostate is treated by surgery in which a portion of the prostate tissue is removed. Another common disorder involving the prostate is prostate cancer. However, some forms of prostate cancer grow very slowly and thus may not ever require treatment.
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