Male Genital Tract Pathology, Part 1

Front 1

What are some pathogens that cause acute prostatitis?

What will you see a common history of in chronic bacterial version?

What are some offenders of chronic "abacterial?"

Back 1

Front 2

How many white men over age 50 have moderate to severe symptoms of nodular hyperplasia (BPH)?

What percent of 60 year olds have it? 70 year old? Are most symptomatic?

Is BPH hypertrophy or hyerplasia?

Is it androgen driven? Is it a precursor to malignancy?

Back 2

Front 3

Prostatic hyperplasia is driven by ______ and is believed to mainly stem from impaired cell death, resulting in the accumulation of ______ cells.

The main androgen in the prostate, constituting 90% of total prostatic androgens, is _______. DHT is formed in the prostate from _________ by type 2 ______. This enzyme is located almost entirely in ____ cells, so they are responsible for androgen-dependent prostatic growth. (Type 1 5α-reductase is not in the prostate, but is in liver and skin and this may produce circulating DHT that acts in the prostate.)

DHT binds to the ________ receptor (AR) present in both stromal and ______ prostate cells. DHT is more potent than testosterone because it has a higher affinity for _____ and forms a more stable complex with the receptor. Binding of DHT to AR stimulates the transcription of _______-dependent genes, most importantly members of the ________ factor (FGF) family and transforming growth factor (TGF)-β. FGFs, produced by ______ cells, are ______ regulators of androgen-stimulated epithelial growth during embryonic prostatic development, and some of these pathways may be “reawakened” in adulthood to produce prostatic growth in ______. TGF-β serves as a mitogen for ________ and other mesenchymal cells, but inhibits _______ proliferation. It is believed that DHT-induced growth factors act by increasing the proliferation of ______ cells and _______ the death of epithelial cells.

Back 3

Prostatic hyperplasia is driven by androgen and is believed to mainly stem from impaired cell death, resulting in the accumulation of senescent cells.
The main androgen in the prostate, constituting 90% of total prostatic androgens, is dihydrotestosterone (DHT). DHT is formed in the prostate from testosterone by type 2 5α-reductase. This enzyme is located almost entirely in stromal cells, so they are responsible for androgen-dependent prostatic growth. (Type 1 5α-reductase is not in the prostate, but is in liver and skin and this may produce circulating DHT that acts in the prostate.)
DHT binds to the nuclear androgen receptor (AR) present in both stromal and epithelial prostate cells. DHT is more potent than testosterone because it has a higher affinity for AR and forms a more stable complex with the receptor. Binding of DHT to AR stimulates the transcription of androgen-dependent genes, most importantly members of the fibroblast growth factor (FGF) family and transforming growth factor (TGF)-β. FGFs, produced by stromal cells, are paracrine regulators of androgen-stimulated epithelial growth during embryonic prostatic development, and some of these pathways may be “reawakened” in adulthood to produce prostatic growth in BPH. TGF-β serves as a mitogen for fibroblasts and other mesenchymal cells, but inhibits epithelial proliferation. It is believed that DHT-induced growth factors act by increasing the proliferation of stromal cells and decreasing the death of epithelial cells.

Front 4

Draw out the pathway of prostatic hyperplasia:

Back 4

Front 5

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Front 6

BPH involves which zone of the prostate? Why does it cause urinary obstruction?

Back 6

Front 7

What is the major clinical problem in those with BPH? What major complications does this lead to (think higher up the tract)?

The most common symptoms of BPH (4)?

2 other non specific symptoms?

Back 7

Front 8

“Mild cases of BPH may be treated without medical or _____ therapy, such as by ______ fluid intake, especially before ______; moderating the intake of ____ and caffeine-containing products; and following timed voiding schedules. The most commonly used and effective medical therapy for symptoms relating to BPH are _____-blockers, which ______ prostate smooth muscle tone via inhibition of _______ -adrenergic receptors. Another common pharmacologic therapy aims to decrease symptoms by physically shrinking the prostate with an agent that inhibits the synthesis of DHT. Inhibitors of ______ fall into this category. For moderate to severe cases recalcitrant to medical therapy, a wide range of more invasive procedures exist. ________ of the prostate (TURP) has been the gold standard in terms of reducing symptoms, improving flow rates, and decreasing post-voiding residual urine. It is indicated as a first line of therapy in certain circumstances, such as recurrent urinary _____. As a result of its morbidity and cost, alternative procedures have been developed. These include high-intensity focused ______, laser therapy, hyperthermia, transurethral _______, and transurethral needle _______ using radiofrequency.”
Robbins and Cotran Pathologic Basis of Disease, ninth edition, 2015, p. 983

Back 8

“Mild cases of BPH may be treated without medical or surgical therapy, such as by decreasing fluid intake, especially before bedtime; moderating the intake of alcohol and caffeine-containing products; and following timed voiding schedules. The most commonly used and effective medical therapy for symptoms relating to BPH are α-blockers, which decrease prostate smooth muscle tone via inhibition of α 1 -adrenergic receptors. Another common pharmacologic therapy aims to decrease symptoms by physically shrinking the prostate with an agent that inhibits the synthesis of DHT. Inhibitors of 5-α-reductase fall into this category. For moderate to severe cases recalcitrant to medical therapy, a wide range of more invasive procedures exist. Transurethral resection of the prostate (TURP) has been the gold standard in terms of reducing symptoms, improving flow rates, and decreasing post-voiding residual urine. It is indicated as a first line of therapy in certain circumstances, such as recurrent urinary retention. As a result of its morbidity and cost, alternative procedures have been developed. These include high-intensity focused ultrasound, laser therapy, hyperthermia, transurethral electrovaporization, and transurethral needle ablation using radiofrequency.”
Robbins and Cotran Pathologic Basis of Disease, ninth edition, 2015, p. 983

Front 9

______ of the prostate is the most common form of cancer in men, who have a one in ______ lifetime probability of being diagnosed with it.
233,000 new cases and 29,480 deaths from it are projected for the US for 2014.
It has a remarkably wide range of clinical behaviors, from very aggressive lethal cancers to incidentally discovered clinically insignificant cancers.

Cancer of the prostate is typically a disease of men over _____. The incidence increases from 20% in men in their 50s to __% in men between the ages of 70 and 80.

Prostatic cancer is uncommon in _____ and most common among _____.

Environment plays a role, as evidenced by the rise in the incidence in _____ immigrants to the US, though not nearly to the level of that of native-born Americans. Increased consumption of ___ or carcinogens present in charred red meats has been implicated. Dietary products suspected of preventing or delaying prostate cancer development include _____ (in cooked tomatoes, for instance), soy products, and vitamin ___.

Back 9

Adenocarcinoma of the prostate is the most common form of cancer in men, who have a one in six lifetime probability of being diagnosed with it.
233,000 new cases and 29,480 deaths from it are projected for the US for 2014.
It has a remarkably wide range of clinical behaviors, from very aggressive lethal cancers to incidentally discovered clinically insignificant cancers.

Cancer of the prostate is typically a disease of men over 50. The incidence increases from 20% in men in their 50s to 70% in men between the ages of 70 and 80.

Prostatic cancer is uncommon in Asians and most common among blacks.

Environment plays a role, as evidenced by the rise in the incidence in Japanese immigrants to the US, though not nearly to the level of that of native-born Americans. Increased consumption of fats or carcinogens present in charred red meats has been implicated. Dietary products suspected of preventing or delaying prostate cancer development include lycopenes (in cooked tomatoes, for instance), soy products, and vitamin D.

Front 10

______ play an important role in prostate cancer . Like their normal counterparts, the ______ and survival of prostate cancer cells depends on ______, which bind to the androgen receptor (AR) and induce the expression of ___-growth and pro-______ genes.

CAG Repeats
The _-linked __ gene contains a polymorphic sequence composed of repeats of the codon CAG (which codes for glutamine). ARs with the ______ stretches of polyglutamine have the highest sensitivity to ______.
The shortest polyglutamine repeats on average are found in __________, while Caucasians have an intermediate length and Asians have the longest, paralleling the incidence and mortality of prostate cancer in these groups.

Back 10

Androgens play an important role in prostate cancer . Like their normal counterparts, the growth and survival of prostate cancer cells depends on androgens, which bind to the androgen receptor (AR) and induce the expression of pro-growth and pro-survival genes.

CAG Repeats
The X-linked AR gene contains a polymorphic sequence composed of repeats of the codon CAG (which codes for glutamine). ARs with the shortest stretches of polyglutamine have the highest sensitivity to androgens.
The shortest polyglutamine repeats on average are found in African Americans, while Caucasians have an intermediate length and Asians have the longest, paralleling the incidence and mortality of prostate cancer in these groups.

Front 11

Molecular mechanisms of resistance to anti-androgen therapy:

The importance of ______ in maintaining the growth and survival of prostate cancer cells can be seen in the therapeutic effect of ______ or treatment with anti­androgens, which usually induce disease ______.

Most tumors eventually become resistant to ______ blockade through acquisition of hypersensitivity to ______ levels of androgen (e.g., through AR gene ______) ligand-independent AR activation (e.g., via splice variants that lack the ligand binding domain) mutations in ___ that allow it to be activated by ______ ligands, and other mutations or epigenetic changes that activate alternative signaling pathways, which may bypass the need for AR altogether including increased activation of the ______ signaling pathway (such loss of the ______ tumor suppressor gene), which is observed most often in tumors that have become resistant to ______ therapy.

Back 11

Molecular mechanisms of resistance to anti-androgen therapy

The importance of androgens in maintaining the growth and survival of prostate cancer cells can be seen in the therapeutic effect of castration or treatment with anti­androgens, which usually induce disease regression.

Most tumors eventually become resistant to androgen blockade through
acquisition of hypersensitivity to low levels of androgen (e.g., through AR gene amplification)
ligand-independent AR activation (e.g., via splice variants that lack the ligand binding domain)
mutations in AR that allow it to be activated by non-androgen ligands, and
other mutations or epigenetic changes that activate alternative signaling pathways, which may bypass the need for AR altogether including
increased activation of the PI3K/AKT signaling pathway (such loss of the PTEN tumor suppressor gene), which is observed most often in tumors that have become resistant to antiandrogen therapy.

Front 12

Familial Risk of Prostate Cancer

Compared with men with no family history, men with one first-degree relative with prostate cancer have _____ the risk and those with two first-degree relatives have ______ times the risk of developing prostate cancer.

Men with a strong family history of prostate cancer also tend to develop the disease at an ______ age.

Men with germline mutations of the tumor suppressor _____ have a 20-fold increased risk of prostate cancer, and a germline mutation in _______ , a homeobox gene encoding a transcription factor that regulates prostatic development, also confers substantially increased risk in the small percentage of families that carry it. However, the vast majority of familial prostate cancers are due to ______ in other loci that confer a small ______ in cancer risk. Family and genome-wide association studies have identified more than 40 risk-associated loci, which explain approximately ___% of the familial risk.

Back 12

Familial Risk of Prostate Cancer

Compared with men with no family history, men with one first-degree relative with prostate cancer have twice the risk and those with two first-degree relatives have five times the risk of developing prostate cancer.

Men with a strong family history of prostate cancer also tend to develop the disease at an earlier age.

Men with germline mutations of the tumor suppressor BRCA 2 have a 20-fold increased risk of prostate cancer, and a germline mutation in HOXB13 , a homeobox gene encoding a transcription factor that regulates prostatic development, also confers substantially increased risk in the small percentage of families that carry it. However, the vast majority of familial prostate cancers are due to variation in other loci that confer a small increase in cancer risk. Family and genome-wide association studies have identified more than 40 risk-associated loci, which explain approximately 25% of the familial risk.

Front 13

What is this? Where is prostatic carcinoma typically located? It is often easier to _____ than see.

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Front 14

Prostate carcinoma diagnosis:

Detected by elevated level of _____ in blood or by physical examination (digital rectal examination)

PSA is ____ (prostate) specific,
but it is NOT _____ specific.
PSA rises in a number of ___ conditions, including BPH and _____.

_____ is essential to make the diagnosis; here is a schematic diagram of the standard procedure for ______ needle biopsy of the prostate:

Back 14

Only 1/10,000 of the prostate removed => high sampling error rate

Front 15

What is shown? Can it be variable in presentation?

What is one features of typical prostate carcinoma?

Back 15

Front 16

Which is normal? Which is prostate cancer? Small glands are a feature of which?

Back 16

Normal gland also has little spindle-looking basal cells around the periphery of the gland.

Front 17

What is shown on the left and the right?

Back 17

Left = perineural invasion

Right = extra capsular extension of the tumor

Front 18

How is the Gleason score calculated?

Back 18

7 and below does much better clinically

1 = best differentiated

5 = worst differentiated

Most predominant + 2nd most predominant

Front 19

1. Prostate biopsies are among the most ______ that pathologists have to diagnose.
2. There is ____ single feature always seen in prostate cancer and never seen in benign prostate.
3. There are only features more ______ in prostate cancer than in normal and features more common in _____ than in prostate cancer.
4. _______ can help reveal loss of the ______ layer of cells in prostate cancer.
5. The presence or absence of the ______ layer of cells in prostate glands, benign or malignant, is never all or nothing (which is an exception to the rule “Never say ‘never’ in medicine.”)
6. Like breast biopsies that are on the borderline between benign and malignant, prostate biopsies on the borderline in the grey zone between benign and malignant can be well worth getting a second opinion from another pathologist for the best diagnosis.

Back 19

Prostate biopsies are among the most difficult that pathologists have to diagnose.
There is no single feature always seen in prostate cancer and never seen in benign prostate.
There are only features more common in prostate cancer than in normal and features more common in normal than in prostate cancer.
Immunostains can help reveal loss of the basal layer of cells in prostate cancer.
The presence or absence of the basal layer of cells in prostate glands, benign or malignant, is never all or nothing (which is an exception to the rule “Never say ‘never’ in medicine.”)
Like breast biopsies that are on the borderline between benign and malignant, prostate biopsies on the borderline in the grey zone between benign and malignant can be well worth getting a second opinion from another pathologist for the best diagnosis.

Front 20

“As a screening test for prostate cancer, the use of ____ remains controversial in that it ______ both sensitivity and specificity.
Although serum levels of _____ are elevated to a lesser extent in BPH than in prostatic ______, there is considerable overlap. Other factors such as _____, infarction of nodular hyperplasias, instrumentation of the prostate, and ______ also increase serum PSA levels.
If the cut-off between normal and abnormal PSA levels is too _____, this may falsely indicate the need for a prostate biopsy in some men and result in the detection and potentially unnecessary treatment of ______ and non–life-threatening tumors.
In most laboratories, a serum level of ___ ng/mL is reported as the cut-off between normal and abnormal, this cut-off may be too high because 20% to __% of patients with organ-confined prostate cancer have a PSA value of __ ng/mL or less, which is not detected by this simple screening test. Thus, some guidelines consider PSA values above ___ ng/mL abnormal.”

Back 20

“As a screening test for prostate cancer, the use of PSA remains controversial in that it lacks both sensitivity and specificity.
Although serum levels of PSA are elevated to a lesser extent in BPH than in prostatic carcinomas, there is considerable overlap. Other factors such as prostatitis, infarction of nodular hyperplasias, instrumentation of the prostate, and ejaculation also increase serum PSA levels.
If the cut-off between normal and abnormal PSA levels is too low, this may falsely indicate the need for a prostate biopsy in some men and result in the detection and potentially unnecessary treatment of indolent and non–life-threatening tumors.
In most laboratories, a serum level of 4 ng/mL is reported as the cut-off between normal and abnormal, this cut-off may be too high because 20% to 40% of patients with organ-confined prostate cancer have a PSA value of 4 ng/mL or less, which is not detected by this simple screening test. Thus, some guidelines consider PSA values above 2.5 ng/mL abnormal.”

Front 21

“Several refinements in the estimation and interpretation of PSA values are currently used. These include the ratio between the serum PSA value and ______ of prostate gland (PSA density), the rate of ______ in PSA value with time (PSA velocity), the use of ___-specific reference ranges, and the ratio of free and ______ PSA in the serum. Men with enlarged ______ prostate glands have higher total serum PSA levels than men with ______ glands. The measurement of serum PSA density factors out the contribution of benign prostatic tissue to serum PSA levels. It is calculated by dividing the total serum PSA level by the estimated gland ______ (usually determined by transrectal ultrasound measurements) to estimate the PSA produced per ______ of prostate tissue. As men age, their prostates tend to enlarge with ______. One would then anti­cipate that, overall, older men would have ______ serum PSA levels than younger men. The upper age-specific PSA reference ranges are ___ ng/mL for men 40 to 49 years of age, ___ ng/mL for men 50 to 59 years, ___ ng/mL for men 60 to 69 years, and ___ ng/mL for men 70 to 79 years. Consequently, a serum PSA value of ___, while it will appear as a normal value on a laboratory test, is a worrisome finding in a man in his 40s, warranting additional evaluation.”

Back 21

“Several refinements in the estimation and interpretation of PSA values are currently used. These include the ratio between the serum PSA value and volume of prostate gland (PSA density), the rate of change in PSA value with time (PSA velocity), the use of age-specific reference ranges, and the ratio of free and bound PSA in the serum. Men with enlarged hyperplastic prostate glands have higher total serum PSA levels than men with small glands. The measurement of serum PSA density factors out the contribution of benign prostatic tissue to serum PSA levels. It is calculated by dividing the total serum PSA level by the estimated gland volume (usually determined by transrectal ultrasound measurements) to estimate the PSA produced per gram of prostate tissue. As men age, their prostates tend to enlarge with BPH. One would then anti­cipate that, overall, older men would have higher serum PSA levels than younger men. The upper age-specific PSA reference ranges are 2.5 ng/mL for men 40 to 49 years of age, 3.5 ng/mL for men 50 to 59 years, 4.5 ng/mL for men 60 to 69 years, and 6.5 ng/mL for men 70 to 79 years. Consequently, a serum PSA value of 3.5, while it will appear as a normal value on a laboratory test, is a worrisome finding in a man in his 40s, warranting additional evaluation.”

Front 22

“Another means of interpreting serum PSA tests is to assess PSA ______ or the rate of ______ of PSA. Men with prostate cancer demonstrate a more rapid ______ in PSA levels over time than do men who do not have prostate cancer. The rate of change in PSA that best distinguishes between men with and without prostate cancer is ____ ng/mL per year. For this measurement to be valid, at least ______ PSA measurements must be performed over a period of 1.5 to 2 years, as there is substantial short-term variability (up to 20%) between repeat PSA measurements. A man who has a significant increase in serum PSA levels, even if the latest serum PSA test is below the normal cut-off (<4 ng/mL), should undergo additional work-up. Studies have revealed that immunoreactive ____ (the form detected by the widely used antibody test) exists in two forms: a major fraction bound to______ -antichymotrypsin and a minor free fraction. The percentage of free PSA (free PSA/total PSA × 100) is lower in men with ______ than in men with benign prostatic diseases.”

Back 22

“Another means of interpreting serum PSA tests is to assess PSA velocity or the rate of change of PSA. Men with prostate cancer demonstrate a more rapid increase in PSA levels over time than do men who do not have prostate cancer. The rate of change in PSA that best distinguishes between men with and without prostate cancer is 0.75 ng/mL per year. For this measurement to be valid, at least three PSA measurements must be performed over a period of 1.5 to 2 years, as there is substantial short-term variability (up to 20%) between repeat PSA measurements. A man who has a significant increase in serum PSA levels, even if the latest serum PSA test is below the normal cut-off (<4 ng/mL), should undergo additional work-up. Studies have revealed that immunoreactive PSA (the form detected by the widely used antibody test) exists in two forms: a major fraction bound to α 1 -antichymotrypsin and a minor free fraction. The percentage of free PSA (free PSA/total PSA × 100) is lower in men with prostate cancer than in men with benign prostatic diseases.”

Front 23

“Other genes that may serve as biomarkers in prostate cancer have emerged. ______is a noncoding RNA which is overexpressed in ______ of prostate cancers. A diagnostic test that quantifies urine PCA3 is currently used as an additional biomarker in patients suspected to have prostate cancer because of elevated______ Elevated urine ______ scores have been shown to be associated with an increased risk of a positive ______ biopsy in this setting. The combination of urinary PCA3 with screening of urine for ______ fusion DNA may have increased sensitivity and specificity compared to PSA screening alone.

Because many small cancers localized to the prostate may never progress to clinically significant invasive cancers, there is considerable uncertainty regarding the management of small lesions that are detected because of an elevated ____ level. This has created controversy about the role of widespread screening for prostate cancer.”

Back 23

Because many small cancers localized to the prostate may never progress to clinically significant invasive cancers, there is considerable uncertainty regarding the management of small lesions that are detected because of an elevated PSA level. This has created controversy about the role of widespread screening for prostate cancer.”

Front 24

In October 2011, the USPSTF posted for public comment the draft of its recommendation regarding prostate cancer screening. Since then, Task Force members have read the many comments received and reviewed the most up-to-date evidence. Based on this work, the Task Force concludes that many men are ______ as a result of prostate cancer screening and few, if any, benefit. A better test and better treatment options are needed. Until these are available, the USPSTF has recommended ______ screening for prostate cancer.
The members of the USPSTF face the same concerns and fears about health challenges as other people. This decision was reached only after extensive consideration and thoughtful debate. It is based on science and rooted in the knowledge that while everyone wants to help prevent deaths from prostate cancer, current methods of PSA screening and treatment of screen-detected cancer are not the answer.
The mission of the USPSTF is to improve the health of all Americans by sharing with them evidence-based recommendations, and empowering them and the clinicians who serve them to make informed decisions

Back 24

In October 2011, the USPSTF posted for public comment the draft of its recommendation regarding prostate cancer screening. Since then, Task Force members have read the many comments received and reviewed the most up-to-date evidence. Based on this work, the Task Force concludes that many men are harmed as a result of prostate cancer screening and few, if any, benefit. A better test and better treatment options are needed. Until these are available, the USPSTF has recommended against screening for prostate cancer.
The members of the USPSTF face the same concerns and fears about health challenges as other people. This decision was reached only after extensive consideration and thoughtful debate. It is based on science and rooted in the knowledge that while everyone wants to help prevent deaths from prostate cancer, current methods of PSA screening and treatment of screen-detected cancer are not the answer.
The mission of the USPSTF is to improve the health of all Americans by sharing with them evidence-based recommendations, and empowering them and the clinicians who serve them to make informed decisions

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Front 26

No screening for men under _____
Individualized decisions about screening for men under ___ at higher risk (AA or positive family history)
Greatest screening benefit ages _____
Every _____ year screening may be preferred to annual screening
No routine screening after age __

Back 26

No screening for men under 40
Individualized decisions about screening for men under 55 at higher risk (AA or positive family history)
Greatest screening benefit ages 55-69
Every two year screening may be preferred to annual screening
No routine screening after age 70

Front 27

Bone metastases are very common. Are they almost always osteoblastic or osteolytic?

Back 27

Osteoblastic!

BLASTIC METASTASES = PROSTATE CANCER!

Front 28

What is shown in this bone metastasis?

Back 28

Reactive bone formation in metastasis due to prostate cancer leads to the dense, “osteoblastic” nodular lesions seen in this metastasis to femur.

Front 29

More than 90% of prostate cancer patients who receive therapy can expect to live for how long?

What is the most common treatment for clinically localized prostate cancer?

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Front 30

Alternative treatments for localized prostate cancer are either ______-beam radiation therapy or _______ radiation therapy, the latter consisting of placing radioactive seeds throughout the prostate (____therapy). External-beam radiation therapy is also used to treat prostate cancer that is too locally ______to be cured by surgery.
Advanced, metastatic carcinoma is treated by ______ deprivation therapy.

Androgen deprivation may be achieved by orchiectomy, or by administration of synthetic analogs of ______ hormone-releasing hormone (LHRH) which suppress normal LHRH, achieving, in effect, a pharmacologic orchiectomy. Other agents decrease levels of local and circulating androgens by inhibiting systemic steroid hormone synthesis.
Finally, ______ blockade of the androgen receptor constitutes an additional means of treatment.

Although androgen deprivation therapy induces remissions, eventually tumors become ______ to testosterone withdrawal, an event that is a harbinger of disease progression and death.

Back 30

Alternative treatments for localized prostate cancer are either external-beam radiation therapy or interstitial radiation therapy, the latter consisting of placing radioactive seeds throughout the prostate (brachytherapy). External-beam radiation therapy is also used to treat prostate cancer that is too locally advanced to be cured by surgery.
Advanced, metastatic carcinoma is treated by androgen deprivation therapy.

Androgen deprivation may be achieved by orchiectomy, or by administration of synthetic analogs of luteinizing hormone-releasing hormone (LHRH) which suppress normal LHRH, achieving, in effect, a pharmacologic orchiectomy. Other agents decrease levels of local and circulating androgens by inhibiting systemic steroid hormone synthesis.
Finally, pharmacologic blockade of the androgen receptor constitutes an additional means of treatment.

Although androgen deprivation therapy induces remissions, eventually tumors become resistant to testosterone withdrawal, an event that is a harbinger of disease progression and death.

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