21st June 2023

Urological and Gynaecological Cancer

Urological malignancies

Prostate cancer

Prostate cancer is now the most commonly diagnosed cancer in the United Kingdom, overtaking the incidence of breast cancer in 2018. It is a cancer associated with advancing age, most diagnosed over the age of 75. There are no clearly identifiable reversible risk factors. There is a greater prevalence in black-African men, and it is least commonly found in Asian men. There are genetic associations with the BRCA2 gene and, to a lesser extent, BRCA1. It is also associated with Lynch syndrome. At present, there is no standard screening program in the UK.

Prostate cancer commonly presents asymptomatically. Men may present with lower urinary tract symptoms, however, this is commonly secondary to benign prostatic hypertrophy, which presents at a similar age and prostate cancer may be found as an incidental finding. The reason for this is that the majority of prostate cancers arise within the peripheral zone of the gland, whereas the urethra runs through the centre of the gland, through the transition zone. Advanced malignancies can present with urinary symptoms, haematuria, haematospermia and symptoms secondary to spread e.g. bony pain. Diagnosis is made using information from a digital rectal examination, serum PSA, MRI of the prostate, biopsies, and staging radiology.

Grading of prostate cancer is quantified using the composite Gleason score, expressed as a primary and secondary pattern e.g. 3+4=7. Prostate cancer has a minimum Gleason score of 3+3=6 and a maximum score of 5+5=10. Lower Gleason grades are no longer considered malignant. Treatments depend on the Gleason grade, TNM staging as well as the age and fitness of the patient.

Radical treatments include surgery, brachytherapy, and radiotherapy. Androgen deprivation therapy is typically co-administered with radiotherapy to reduce local and distant recurrence. Androgen deprivation is the foundation of treatment in advanced disease. In addition to this, novel oral antiandrogen therapies, chemotherapy, radiotherapy, and radium treatment have roles in the management of advanced disease.

Bladder cancer

Bladder cancer typically presents with haematuria in approximately 80% of cases. Other symptoms include a change in urinary habit (e.g. frequency), dysuria and systemic manifestations including pain and weight loss. Most bladder cancers in the UK are urothelial carcinomas (previously termed transitional cell carcinomas, but this nomenclature is still used in common practice). Squamous cell carcinomas are less common and are typically found in the context of chronic infections.

Bladder cancers are associated with smoking, age, chronic infections, and occupational exposures. The MRCP candidate may realise that questions pertaining to common pathologies focus on the rarer, more interesting aspects of those diseases. So it is wise to remember the occupational exposures, despite their relative rarity, as these will appear in the question stems! These include arylamines, banned for over 50 years in the UK, but exposure is seen in those working in industries dealing with dyes, rubber, and plastics. Polycyclic aromatic hydrocarbons (PAH) exposure may be seen in those working with crude oil or those working nearby sources of combustion (e.g. smelting). Likewise, in parts of the world where schistosomiasis is endemic (e.g. Egypt), squamous cell carcinomas are the most common bladder cancers, so do not ignore information in the stem about the patient’s country of origin.

Treatment for bladder cancer ranges from transurethral resection of bladder tumours (TURBT), intravesical BCG administration (the very same given for TB vaccination), radical cystectomy and radical chemoradiotherapy. Neoadjuvant chemotherapy has an established role to reduce the risk of recurrence prior to radical surgery or chemoradiotherapy (5% 5-year overall survival benefit). Palliative treatments include chemotherapy, immunotherapy, and radiotherapy.

Renal cancer

Renal cancers are differentiated between those of the renal parenchyma (renal cell carcinoma), renal tract (urothelial carcinomas; formerly transitional cell carcinoma) as well as rarer entities including Wilms’ tumours and neuroblastoma. Increasingly, they present as an incidental finding on imaging for other reasons. They can present with flank/back pain, masses, haematuria, recurrent infections, and weight loss.

Surgery remains the mainstay of radical treatment for malignancies of the renal tract. There is no established role for neoadjuvant or adjuvant therapy for renal cell carcinomas, although this is the subject of clinical trials. There is a role for adjuvant chemotherapy for upper tract urothelial malignancies, as per bladder cancer. Management of metastatic disease includes immunotherapy as well as various tyrosine kinase inhibitors.

Questions within the part 1 exam pertaining to malignancies of the renal tract tend to focus on familial syndromes. As a more general tip, it would be wise to revise the more common familial cancer syndromes. For renal malignancies these syndromes include:

• Von Hippel-Lindau syndrome – Caused by a pathological mutation of the VHL gene. Results in clear cell carcinoma of the kidney as well as haemangioblastomas of the central nervous syndrome, phaeochromocytomas, inner-ear tumours and neuroendocrine tumours of the pancreas.
• Tuberous sclerosis – Caused by a pathological mutation of the TSC1 & TSC2 genes. Results in angiomyolipomas of the kidney and subependymal giant cell astrocytomas. Other manifestations include ungual/periungual fibromas, facial angiofibroma and hypomelanotic macules.
• PTEN hamartoma syndrome – Caused by a pathological mutation of the PTEN gene causing clear cell carcinomas as well as associations with breast and thyroid cancer. Patients exhibit macrocephaly, mucocutaneous papules, hamartomas, and lipomas.
• Birt-Hogg-Dube syndrome – Caused by a pathological mutation of the FLCN gene causing oncocytic and chromophobe renal cell carcinomas as well as lung cysts and fibrofolliculomas.

Testicular cancer

Testicular cancer presents with a bimodal age distribution with peaks aged between 15-35 for tumours arising from germ-cell origins including teratoma, whereas seminoma, which arises from the germinal epithelium of the seminiferous tubules, typically presents over the age of 35. Patients typically present with a testicular mass, pain or features of distant disease including back pain, fevers, and weight loss. The incidence of testicular cancer has been increasing since the 1990s, however, the aetiology of this is unclear.

Tumour markers in germ-cell tumours include beta-HCG, alpha-fetoprotein and LDH and are useful in their diagnosis and prognostication. Importantly, AFP is never raised in seminoma. (Please note in the exam, to be wary of answers that include the key phrases ‘never’ and ‘always’ as they are usually incorrect; little in Medicine is black and white). If AFP is elevated in the context of a known seminoma, consider whether there is dual pathology or a misdiagnosis. Other causes of a raised AFP can include hepatocellular carcinoma, cirrhosis, and hepatitis. If no alternative cause for the AFP rise is found, there is likely incomplete/incorrect histological diagnosis and so this malignancy should be treated as a non-seminomatous germ-cell tumour (NSGCT), where mixed pathology is likely to be present. The treatment differs depending on whether the germ-cell tumour is seminomatous or non-seminomatous.

Management of the primary cancer is typically with a radical orchidectomy, and further adjuvant treatment is based on tumour markers and histological features. Surveillance versus adjuvant chemotherapy is considered for early disease. Lymph-node positive and metastatic disease is typically treated with chemotherapy initially, prior to orchidectomy (unless distant disease is identified after the initial surgery). Chemotherapy regimens for advanced disease typically involve bleomycin, epirubicin and cisplatin (shortened to BEP). Even in patients with metastatic disease, cure rates remain >90%.

Although it is unfair to expect a working understanding of the practicalities and side effects of chemotherapy, these questions do arise. There are common tropes with certain chemotherapy agents. Some of these are listed below, please note not all of these agents will be employed in germ-cell tumours:

• Platinums (e.g. cisplatin, carboplatin and oxaliplatin): Notable side effects include neutropenia, nausea, ototoxicity, nephrotoxicity, peripheral neuropathy, and venous thrombo-embolic disease.
• Bleomycin: Notably causes ‘bleomycin lung’ which can manifest as profound pulmonary fibrosis, which can be devastating in such a young population. The risk of pneumonitis is increased in those older than 40, with pre-existing pulmonary disease, renal impairment or undergoing high-flow oxygen therapy.
• Alkylating agents (e.g. cyclophosphamide, ifosfamide, temozolomide): Notable side effects include alopecia, neutropenia (+/- pancytopenia) & diarrhoea.
• Antimetabolite agents – this is a diverse group of agents, targeting metabolites of DNA/RNA synthesis
  • Capecitabine or 5-fluorouracil: Notable risks include profound, life-threatening diarrhoea, palmar-plantar erythrodysesthesia (PPE) and coronary artery vasospasm, particularly in the presence of pre-existing dihydropyrimidine dehydrogenase deficiency (DPD).
  • Methotrexate: Associated with pancytopenia, pulmonary fibrosis, hepatotoxicity, nephropathy

Gynaecological malignancies

Uterine cancer

Cancer of the uterus typically presents early due to the presence of post-menopausal or irregular menstrual bleeding, present in 90% of cases. The risk of uterine cancer increases with age, with a peak of cancers diagnosed between ages 40-74. Oestrogen has a pivotal role in the genesis of uterine malignancy as it causes the cells of the endometrium to grow and divide. Related risk factors include obesity, due to the presence of greater levels of oestrogen as a result of increased production of the enzyme aromatase, which peripherally converts circulating androgens into oestrogens. Early menarche and late menopause increase exposure to oestrogen. Hormone replacement therapy and tamoxifen are also implicated. Risk is also elevated in those with Lynch syndrome.

The primary treatment in early-stage disease is a simple hysterectomy. Vaginal vault brachytherapy, external beam radiotherapy and chemotherapy have roles to reduce the risk of recurrence. Chemotherapy, immunotherapy, and radiotherapy have a role in the management of metastatic disease as well as progesterone in the management of ER+ve disease.

Cervical cancer

Cancers of the cervix may present with abnormal vaginal bleeding, dyspareunia, vaginal discharge, pelvic pain or asymptomatically through the national screening programme. NHS screening in England is currently offered every three years between the ages 25-49 and every 5 years between the ages 50-64 to everyone with a cervix. The programme differs across the UK and so questions on the frequency of screening are unlikely to feature in the exam. High-risk HPV infection is found in association with >99% of cervical cancers and therefore is the primary test on the screening sample. HPV negative samples are not further tested. Those found to have a mild dyskaryosis will be invited for a repeat smear as the majority of these changes regress spontaneously. Those with moderate-high grade dyskaryosis will be invited for a colposcopy for diagnosis +/- treatment.

The majority of cervical cancers are squamous cell carcinoma, with adenocarcinoma accounting for 10-15% of cases. Surgical options are the mainstay of treatment for small, organ-confined tumours (<4cm). For patients with very small tumours, fertility-sparing treatments can be offered in the form of a LLETZ (large loop excision of the transformation zone) or trachelectomy. For those tumours >4cm or those which have invaded beyond the cervix, radical treatment is pursued with radical chemoradiotherapy followed by brachytherapy. The management of metastatic disease includes chemotherapy, radiotherapy, and an emerging role for immunotherapy.

Ovarian cancer

Cancers of the ovary are subdivided into the cell of origin. The majority are epithelial in origin, and this also encompasses malignancies of the Fallopian tube and peritoneum. Epithelial cancers are further subdivided into serous carcinoma, endometrioid (linked to endometriosis), clear cell (also linked to endometriosis) and mucinous. The latter should be differentiated from metastatic spread from a mucinous gastrointestinal primary and typically the appendix is resected during surgery to rule this out as a primary site.

Germ-cell tumours are less common but should be suspected in patients presenting at a young age. These can be divided into benign tumours (e.g. mature teratoma) and malignant tumours including dysgerminomas (the ovarian equivalent of seminomas), yolk sac tumours and choriocarcinomas.

Sex-cord stromal tumours are rare entities, making up 5% of ovarian cancers. They originate from the supportive structures of the ovary and can be functional, secreting excessive androgens and oestrogens. Therefore, these may present with dysfunctional menstrual bleeding, post-menopausal bleeding, and breast tenderness.

In those with suspected cancer, the Risk of Malignancy Index (RMI) is employed. This is calculated using the formula RMI = CA125 x U x M. CA125 is a serum tumour marker which is non-diagnostic but is often raised in ovarian malignancy. U confers a score based on ultrasound features, with 1 point for each of the following characteristics: multilocular cysts, solid areas, metastases, ascites, and bilateral lesions. U = 0 (for an ultrasound score of 0), U = 1 (for an ultrasound score of 1), and U = 3 (for an ultrasound score of 2 to 5). M confers the menopausal status, with a score of 1 for pre-menopausal patients and 3 for post-menopausal patients. Referral onwards for specialist review should be triggered in those patients with an RMI of 250 or more.

Treatment for ovarian cancer is typically with surgery, guided by the extent of the disease, ranging from a simple oophorectomy, to total macroscopic clearance of disseminated disease, as well as exenterative surgery. Neoadjuvant or adjuvant chemotherapy is guided by the staging and characteristics of the underlying malignancy.