24. Urologic and male genital cancers
Prostate cancer
Prostate cancer is the most common form of cancer in men, accounting for around 25% of cases. However, it causes only 9% of all cancer deaths, which shows that it has a low mortality. This is owed mostly to regular screening of PSA levels and digital rectal examination and that we have relatively effective treatment. Prostate cancer is mostly a disease of elderly. About 1 in 8 men will be diagnosed with prostate cancer at some point of their lives, but autopsy studies have shown that many more than this actually develop prostate cancer, but that it remains too small to be significant.
Management may involve local radiotherapy, radical prostatectomy, or "active surveillance" (giving no treatment but monitoring closely for progression). Prostate cancer is usually not aggressive and has a good prognosis, which allows for the watchful waiting approach. A commonly known saying is that "more men die with prostate cancer than because of it".
Risk factors
The following are risk factors for developing prostate adenocarcinoma:
- Age > 50 years
- Positive family history
- African-American ethnicity
- Scandinavian ethnicity
- Obesity
- Diet high in animal fat
Benign prostatic hyperplasia is not a risk factor for prostate cancer.
Importantly, because the peripheral zone is not removed during simple prostatectomy or TUR-P, prostate cancer can still develop after these procedures (which are used for BPH).
Pathology
95% of prostate cancers are acinar adenocarcinomas, the remaining neuroendocrine tumours and sarcomas. Adenocarcinomas develop from the peripheral zone. The cells of the cancerous prostatic glands have prominent nucleoli and show atypia. These glands are small and are also not surrounded by basal cells, unlike the healthy prostatic glands. Prostate cancer has a long doubling time.
Metastasis
Prostate cancer is relatively indolent, generally not metastasising often. When it does, metastasis to bone and liver are most common.
Gleason grading
Grading depends on the Gleason system, which assigns each case a “score” based on their histology. Prostate cancers are divided into 5 grades, depending on the glandular architecture (and not the nuclear atypia). In grade 1 the glands look almost like normal glands while in grade 5 there are only a few or no glands (correspond to anaplasia).
Clinical features
Prostate cancer usually does not cause symptoms in the early stages. As most (70 – 80%) prostate cancer grows in the peripheral zone of the prostate, lower urinary tract symptoms are rarely seen until the later stages, when the cancer has grown. Advanced-stage prostate cancer may present with general cancer symptoms like fatigue and loss of appetite.
Prostate cancer most frequently metastasizes into the spine, especially the lumbosacral part, causing lower back pain. It also metastasizes to parailiac lymph nodes.
Diagnosis and evaluation
The diagnosis may be suspected based on digital rectal examination (DRE) and serum PSA. Those 70 – 80% of cancers that occur in the peripheral zone may be discovered during routine digital rectal examination screening; most prostatic cancers aren’t palpable on DRE though. Definitive diagnosis is based on needle biopsy of the prostate.
Multiparametric MRI (mp-MRI) is a form of MRI which combines multiple MRI modalities to assess the prostate for cancer better than a "regular" MRI can.
Transrectal ultrasound may be used in the evaluation of prostate cancer to calculate the prostate volume and to guide biopsy.
PSA
Main article: PSA
Prostate-specific antigen (PSA) is an enzyme that is produced only by the prostatic glandular epithelium, which is why its level correlates to the number of prostatic glands in the body. Its level can also be increased in prostatitis or BPH, so it’s not specific for cancer. PSA is considered elevated above 4 ng/mL, but there is no level of PSA which is definitely associated with prostate cancer which requires treatment.
It is uncertain whether PSA screening actually decreases prostate-cancer related deaths. Elevated PSA might not necessarily correlate to a clinically active cancer, so its usefulness should be determined on a case-by-case basis. PSA does have great value in measuring the effectiveness of therapy though.
In addition to measuring the total level of PSA, one can also measure other parametres such as free PSA, PSA density, PSA velocity, complexed PSA, and percentage of [-2]proPSA (a precursor of PSA). While decreased free PSA is known to be more specific for prostate cancer than total PSA, the clinical utility of the other parametres is not yet established and so they're not much used.
Staging
- T1 – incidental finding
- Not palpable or visible on imaging
- Present biochemically (as elevated PSA)
- T2 – localized cancer
- Localized to prostate
- T3, T4 – locally advanced cancer
- N+ or M+ – metastatic cancer
Treatment
In many cases of prostate cancer an “active surveillance” approach might be safer than outright treating the tumor. This is especially true for elderly people with comorbidities or people with a less than 10-year life expectancy, as the treatment might be worse than the disease.
For low-risk prostate cancer, active surveillance and surgery have the same outcome. For intermediate and high-risk disease, surgery has better outcome than surveillance. For intermediate-risk disease, radiotherapy and surgery have similar outcomes and odds of cure.
Metastatic prostate cancer cannot be cured. Palliative options include chemotherapy and hormonal therapy.
Active surveillance
Active surveillance is the preferred option for most prostate cancer which are low or low-intermediate risk. It involves routinely measuring PSA and repeating mp-MRI to assess for progression. If there is sign of progression, active therapy can be considered.
Active surveillance helps avoid cancer treatment which may be unneccessary, as low and low-intermediate risk prostate cancer may never metastasise or become symptomatic. However, the patient must live with the uncertainty that the cancer may progress.
Surgical therapy
Surgical treatment of the prostate involves laparoscopic radical prostactetomy (RP), the complete surgical removal of the prostate. Radical prostatectomy has better outcomes when performed robot-assisted. RP is only performed if one expects to achieve cure.
This surgery usually severs autonomic cavernous nerves which control erectile function, thereby almost always causing impotence as a side effect. Another common side effect is urinary incontinence, but this usually improves over time.
Radiotherapy
Radiotherapy is a potentially curative modality for prostate cancer, but prostate cancer requires a very high load of radiation for local control, up to 100 Gy total. Radiotherapy may be performed with external beam (EBRT) or high dose rate brachytherapy (HDBRT), but external therapy is most common.
Before radiotherapy, small seeds of gold are inserted into the prostate. Because these are clearly visible on imaging, this allows for more precise radiation planning.
Radiotherapy also has impotence as a common side effect.
Watchful waiting
Watchful waiting is different from active surveillance in that there is no routine evaluation for progression, and is an option for asymptomatic or mildly symptomatic prostate cancer. With watchful waiting, one undergoes no treatment but if symptoms occur or progress, one can consider palliative treatment.
Chemotherapy
Chemotherapy is indicated as palliation for metastatic prostate cancer. Commonly used drugs are docetaxel and cabazitaxel.
Castration/ADT
Castration, also known as androgen deprivation therapy (ADT), is the anatomical or functional loss of the testicals. It may be achieved by orchidectomy or by use of GnRH agonists or antagonists. ADT is usually combined with an antiandrogen like abiraterone or enzalutamide.
ADT is usually indicated as neoadjuvant therapy before curative radiotherapy as well as adjuvant therapy after. Hormones make the cancer cells more radiosensitive and decreases the tumour size. Common side effects include erectile dysfunction, as well as typical symptoms of menopause like hot flashes, night sweats, mood changes, and decreased libido. However, these side effects are reversible when hormonal therapy is finished. It may also be used as palliation for metastatic prostate cancer.
Screening
The efficacy of screening for prostate cancer is debated. The reason for this is that not all cases of prostate cancer are aggressive and fatal; many cases follow a very indolent course with few clinical symptoms. Screening (especially with PSA) can’t differentiate between prostate cancers that would become aggressive and those that wouldn’t, and so many people who would develop clinically indolent prostate cancer undergoes potentially life-changing treatment which may be worse than the symptoms of the cancer would have been. Indeed, prostate cancer is often found incidentally on autopsy, and more people die with prostate cancer than of prostate cancer.
In Norway, there is no national screening programme for prostate cancer. In Hungary, the lecture recommends annual DRE and PSA measurement for men older than 50, but there is no national screening programme (as far as I can see).
Bladder cancer
Bladder cancer is the most common cancer of the urinary system. The most common histological type is urothelial carcinoma, previously called transitional cell carcinoma (90% of cases), and 90% of urothelial carcinoma cases are in the bladder. The other histological types of bladder cancer are squamous cell carcinoma and adenocarcinoma.
Urothelial carcinoma can occur anywhere there is urothelium, although it occurs most commonly in the bladder and renal pelvis and more rarely in the ureters and urethra. It's usually asymptomatic in early stages, and the most common presenting symptom is painless gross haematuria, which is present in 80% of bladder cancer patients.
Bladder cancer is mostly a disease of older men. In the majority of cases, the disease is not muscle-invading and therefore has high chances of cure and good prognosis.
Risk factors
Urothelial carcinoma is the second most frequent cancer in smokers, after lung cancer of course. This is because the urothelium is exposed to the toxins in the cigarette smoke after it has been excreted by the kidney. It’s also associated with occupational toxins like aromatic hydrocarbons and arsenic. Other risk factors include:
- Lynch syndrome
- Family history of urothelial cancer
- Previous radiation to the pelvis
Squamous cell bladder cancer is related to urinary schistosomiasis (a parasite specially in endemic countries like Egypt), chronic bladder irritation and infection.
Pathology
90% of bladder cancer cases are urothelial carcinoma, previously called transitional cell carcinoma.
Polychronotropy
Urothelial carcinoma shows polychronotropy, which means that when one urothelial carcinoma is found it is very likely that other urothelial tumors are present or currently developing at other places of the mucous membrane. Because of this, urothelial carcinoma has a high risk of recurrence.
Other histological types
Adenocarcinoma is rare and histologically identical to gastrointestinal adenocarcinomas.
Squamous cell carcinoma is rare and related to chronic inflammation of the bladder, especially schistosomiasis.
Clinical features
The most common symptom is painless gross haematuria. There may also be symptoms of bladder irritation, like dysuria, pollakisuria, and urgency.
Some may present as incidentally discovered microscopic haematuria (defined as 2+ or more on a urinanalysis on 3 separate urine tests with 1 month between the tests).
Bimanual examination (one hand per rectum and the other in the vagina (women) or lower abdominal wall (men) can be used to palpate for evidence of local extension of bladder cancer, which is usually evident of muscle-invasive disease.
Diagnosis and evaluation
Haematuria on urine analysis is seen in most cases of bladder cancer. Urine cytology may show cancer cells.
Patients suspected of having bladder cancer should be referred to cystoscopy. Cystoscopy allows for taking biopsy sample, cytology sample, or even resecting the tumour in its entirety in some cases.
CT with contrast is the first choice imaging modality if bladder cancer is suspected based on cystoscopy. It allows for visualisation of the local spreading of the malignancy and to look for other tumours as urothelial carcinoma is often multifocal. Because contrast is filtered by the kidneys, it enters the urinary tract, and a tumour may therefore produce a filling defect. If the tumour has invaded the bladder wall, it will appear thickened on the CT. CT urography also allows for examination of the entire urinary tract, as bladder cancer is often multifocal. CT abdomen and pelvis to look for metastasis is also indicated for staging. In Norway, CT of the abdomen is performed before cystoscopy (because positive findings may allow the patient to skip cystoscopy and proceed directly to TUR-B).
Stages
Non-muscle invasive bladder cancer (NMIBC), also called stage I, refers to when the disease has not invaded the muscle of the urinary bladder. Muscle-invasive disease (MIBC) may be stage II or III, depending on how far it has spread locally. Metastatic disease is stage IV, where metastasis is present.
Non-muscle invasive and muscle-invasive disease can only be distinguished by transurethral resection of the bladder or by MRi. CT cannot distinguish them.
Management
Management for non-metastatic disease (stages I - III) involves either cystoscopic surgical removal of the tumour (TUR-B), complete surgical removal of the bladder (radical cystectomy), or radiotherapy + chemotherapy. For metastatic disease, only chemotherapy and/or immunotherapy is indicated.
Transurethral resection of the bladder
Transurethral resection of the bladder (TUR-B) is a cystoscopic procedure where the tumour and surrounding bladder tissue are removed with a transurethral resectoscope. After the resection, chemotherapeutical drugs or BCG are instilled into the bladder to reduce any residual cancer cells.
TUR-B is both diagnostic and therapeutic and is indicated for all stages of bladder cancer. If the histological examination following TUR-B shows no muscle invasion and shows complete removal, the patient should receive regular installation of chemotherapy or BCG in the bladder for months/years. If there is evidence of muscle invasion, radical cystectomy or bladder preservation therapy is indicated.
Radical cystectomy
Radical cystectomy is indicated for muscle-invasive disease. It involves removal of the bladder, prostate, seminal vesicles, uterus, and adnexae. Lymph node dissection should also be performed. Without a bladder, a bladder substitute should be made. There are multiple options:
- An ileal conduit urinary diversion, also called a Bricker conduit. A new bladder is made from part of the ileum, with the ureters connected to one end, and the other end opens through the abdominal wall like an enterostoma. Urine is collected in a bag connected to the stoma. This is the most common option
- Continent cutaneous urinary diversion. A reservoar for urine is made from a portion of the bowel remade to be like a "sack", which is opened to the abdominal wall. To empty the reservoar of urine, the opening must be catheterised with aseptic technique.
- Continent orthotopic diversion or neobladder. It is similar to an ileal conduit except that the urethra is connected to the new bladder, which allows urination through the urethra as normal.
Bladder preservation therapy
Bladder preservation therapy, also called trimodal treatment, refers to extensive TUR-B followed by radiochemotherapy. This option preserves the bladder.
BCG
BCG (Bacille Calmette-Guérin) is a live vaccine used to prevent tuberculosis. Somehow someone discovered that administering it into the bladder acts like an immunotherapy, where it stimulates the immune system to kill the cancer cells. It may be administered into the bladder following TUR-B for non-muscle-invasive disease.
Chemotherapy
Chemotherapy is usually a combination of gemcitabine and cisplatin. It is indicated as part of bladder preservation therapy or for palliation in metastastic disease.
Immunotherapy
Immunotherapy, usually with immune checkpoint inhibitors like anti-PD-L1 or anti-PD-1 antibodies, is indicated for palliation in metastatic disease.
Radiotherapy
Radiotherapy may be part of bladder preservation therapy or be used palliatively for metastatic disease.
Renal cancer
Testicular cancer
Testicular cancer is most frequent in young males. It is the most common tumor in men in the 15 – 35 age group. There are three age peaks where testicular cancer is most common:
- 15 – 35 years (the most common age group)
- 0 – 10 years
- > 60 years
96% of all testicular tumors are malignant. Most present with metastases already present, but despite this the prognosis is excellent. Even advanced and metastatic testicular cancers are often curable. Overall the cure rate is 80 - 90%. Most (95%) of testicular malignancies are germ cell tumours, which originate from germ cells, the majority of these are seminomas.
Risk factors
Most are idiopathic, but some known risk factors exist:
- Cryptorchidism
- Previous testicular cancer
- Positive family history
- Gonadal dysgenesis
- Klinefelter syndrome
- Down syndrome
Pathology
95% of testicular tumors originate from germ cells. The remaining 5% originate from the testicular stroma (which is derived from the sex cords), including Sertoli cells, Leydig cells or granulosa cells.
Germ cell tumours
Germ cell tumors develop from totipotent germ cells. During embryonal development these totipotent cells can travel down normal differentiation pathways and become spermatocytes. However, if they instead travel down abnormal developmental pathways, they can become seminomas or embryonal carcinomas. Germ cell tumors account for 95% of all testicular tumors. It’s very common (in 60% of cases) for germ cell tumors to contain more than one histological subtype. These are called mixed germ cell tumors. The remaining 40% of cases are pure germ cell tumors and contain only one histological subtype.
Most germ cell tumor develop from a precancerous lesion called germ cell neoplasia in situ (GCNIS). This precancerous lesion is virtually always present together with the mature GCNIS-derived germ cell tumor when examined histologically. This lesion has a 50% chance of progressing into cancer within 5 years.
GCNIS-derived germ cell tumours
Seminoma is the most common pure testicular germ cell tumor. It most frequently occurs in patients in their 40s. Seminomas grow slowly and rarely metastasize, and therefore have a better prognosis than non-seminomas. It also has a good radiosensitivity, meaning that it’s highly treatable by irradiation. Seminomas are homogenous masses with small foci of haemorrhage or necrosis. Some cases of seminoma can produce hCG.
Sex cord stromal tumours
These tumors account for 5% of all testicular tumors in adults, but they are much more frequent in childhood. These tumors arise from Leydig cells, Sertoli cells or granulosa cells. They are usually benign.
Lymphoma
Lymphomas may occur in the testes as well, most frequently as diffuse large B-cell lymphoma (DLBCL). These are the most frequent testicular tumors in men older than 60.
Clinical features
Testicular tumors usually present as incidentally discovered firm, painless masses on the testis. Unlike hydroceles, these masses cannot be transilluminated. In case of metastases there may be symptoms like cough, chest pain, or bone pain.
Diagnosis and evaluation
The first diagnostic step for a testicular mass is ultrasound and physical examination. If these raise suspicion for malignancy, we proceed to orchidectomy.
Testicular masses are never biopsied, unlike most suspected tumors elsewhere in the body. Instead, sperm is cryopreserved, and the testis is removed by orchiectomy. Because the vast majority of testicular tumors are malignant there is a high chance the testis would have been removed anyway. Also, biopsying a malignant testicular tumor could allow tumor cells to seed in the scrotum.
CT of the thorax, abdomen, and pelvis should be made to look for spread, either before or after orchidectomy, but preferably before. This is necessary for staging. MRi of the brain is indicated if brain metastases are suspected.
Tumour markers
AFP, hCG, and LDH are important tumor markers in testicular tumors. Different histological subtypes have different patterns of expression of these tumor markers. Seminomas often do not have elevated tumour markers.
Hormone analysis
Before orchidectomy, we also measure hormone levels.
Stages
Limited disease refers to cancer which is limited to the testicles. Locally advanced disease is when there is involvement of the retroperitoneal lymph nodes, usually the para-aortic lymph nodes. Metastatic disease is when there is evidence of metastasis.
Management
All patients with suspected testicular cancer on ultrasound and physical examination should undergo surgical exploration. If surgery and intraoperative frozen histology sections cannot rule out malignancy, orchidectomy is performed. This allows for histological examination and complete staging and risk stratification. However, at no point should the urologic surgeon incise the tumour itself, for risk of seeding. A testicular prosthesis can be placed at the same time. If there is sign of retroperitoneal lymph node involvement (most commonly the para-aortic lymph nodes), retroperitoneal lymph node dissection (RPLND) is indicated.
Localised disease with no high-risk features can usually be followed with active surveillance after surgery, but if there is intermediate or high-risk, adjuvant chemotherapy is recommended. In locally advanced disease, adjuvant radiotherapy or chemotherapy is indicated. For metastatic disease, adjuvant chemotherapy is indicated.
Organ sparing surgery
Organ sparing surgery, i.e. the resection of a tumour instead of complete orchidectomy, may be an option if the cancer affects both testicles or the patient only has one testicle and it is affected. The goal is to maintain the endocrine function of the testicles. Adjuvant radiotherapy is always indicated.
Biopsy of contralateral testicle
During orchidectomy, we may perform a biopsy of the contralateral (healthy-looking) testicle. This is to look for GCNIS (cancer in situ). This biopsy is indicated if the cancer is a germ cell tumour or there are risk factors of GCNIS, such as cryptorchidism or an atrophic testicle.
Chemotherapy
Chemotherapy is indicated if there is metastatic disease. It's usually a combination of cisplatin, etoposide, and bleomycin.
Radiotherapy
Seminomas are very radiosensitive, whereas non-seminomas are only moderately radiosensitive. For this reason, radiotherapy is mostly only used for seminomas. Radiotherapy is less and less used nowadays in favour of chemotherapy.