Urologic Cancer

Urologic cancer is a broad term that involves cancer of the male and female urinary tracts and male reproductive organs. Risk factors for urologic cancer are smoking; exposure to chemicals such as benzidine and beta-naphthylamine, and arsenic; genetic predisposition; and chronic irritation of the urinary system. Clinical presentation includes painless hematuria, flank and/or suprapubic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, dysuria, and unexplained significant weight loss. The gold standard for diagnosis is endoscopy of the urologic structures (cystoscopy, cystourethroscopy, ureteropyeloscopy) with biopsy. Additional studies include radiologic imaging, which gives information about the tumor invasion and spread of the disease to other sites or organs. Management includes surgery, chemotherapy, radiotherapy, and supportive treatment, depending on the location, extent, and histology.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Growth of abnormal cells from the lining of organs of the male and female urinary tracts and the male reproductive organs.

Epidemiology

  • Bladder cancer is the most common urologic cancer.
  • Incidence in men is 4x more than that in women.
  • The incidence of bladder cancer increases with age, with a median age at diagnosis of 73 years.

Risk factors

  • Smoking tobacco (most common risk factor for urothelial bladder cancer in the United States)
  • Long-term exposure to chemicals (benzidine, heavy metals, aniline dye, and beta-naphthylamine) 
  • Age > 55 years
  • Chronic urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation due to:
    • Schistosomiasis Schistosomiasis Schistosomiasis is an infection caused by Schistosoma, a trematode. Schistosomiasis occurs in developing countries with poor sanitation. Freshwater snails are the intermediate host and are transmitted to humans through skin contact with contaminated fresh water. The clinical presentation occurs as a result of the host's immune response to antigens from the eggs. Schistosoma/Schistosomiasis infection of the bladder
    • Recurrent or chronic urinary tract infections Urinary tract infections Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary Tract Infections
    • Renal fibrosis from Chinese herbs (especially those that contain aristolochic acid), nephropathy
    • Balkan endemic nephropathy (inflammatory process of the renal interstitium noted in the Balkan region)
  • History of exposure to radiation in the pelvic area 
  • Previous treatment with cyclophosphamide 
  • Use of phenacetin (analgesic)
  • Arsenic in drinking water
  • Genetic predisposition: 
    • Mutations in the RB1, TP53, or PTEN gene
    • Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome (hereditary nonpolyposis colorectal cancer Colorectal cancer Colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths in the United States. Colorectal cancer is a heterogeneous disease that arises from genetic and epigenetic abnormalities, with influence from environmental factors. Colorectal Cancer ( HNPCC HNPCC Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome))
  • Exposure to human papillomavirus Human papillomavirus Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV ( HPV HPV Human papillomavirus (HPV) is a nonenveloped, circular, double-stranded DNA virus belonging to the Papillomaviridae family. Humans are the only reservoir, and transmission occurs through close skin-to-skin or sexual contact. Human papillomaviruses infect basal epithelial cells and can affect cell-regulatory proteins to result in cell proliferation. Papillomaviridae: HPV-16)

Types

  • Urinary bladder cancer
  • Renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma 
  • Testicular cancer Testicular cancer Testicular cancer is the most common solid malignancy affecting men 15-35 years of age. Most of the testicular cancers are of the germ cell tumor type, and they can be classified as seminomas and nonseminomas. The most common presentation of testicular cancer is a painless testicular mass. Testicular Cancer
  • Penile cancer Penile cancer Malignant lesions of the penis arise from the squamous epithelium of the glans, prepuce, or penile shaft. Penile cancer is rare in the United States, but there is a higher prevalence in lower socioeconomic regions. The most common histologic subtype is squamous cell carcinoma. Penile Cancer 
  • Urethral cancer 
  • Ureteral cancer 
  • Prostate cancer Prostate cancer Prostate cancer is one of the most common cancers affecting men. In the United States, the lifetime risk of being diagnosed with prostate cancer is approximately 11%, and the lifetime risk of death is 2.5%. Prostate cancer is a slow-growing cancer that takes years, or even decades, to develop into advanced disease. Prostate Cancer

Bladder Cancer

Histologic types

  • Urothelial carcinoma:
    • Previously known as transitional cell carcinoma
    • Urothelial cells physiologically expand and contract when the bladder is full and empty, respectively.
    • Most common type of bladder cancer in the United States
  • Squamous cell carcinoma Squamous cell carcinoma Cutaneous squamous cell carcinoma (cSCC) is caused by malignant proliferation of atypical keratinocytes. This condition is the 2nd most common skin malignancy and usually affects sun-exposed areas of fair-skinned patients. The cancer presents as a firm, erythematous, keratotic plaque or papule. Squamous Cell Carcinoma
    • Associated with chronic bladder irritation
    • Commonly occurs in countries where the incidence of schistosomiasis is high 
  • Adenocarcinoma: 
    • Occurs in mucus-secreting cells of the bladder
    • Rare type

Clinical presentation

  • Painless gross hematuria (classic presentation), which can differ depending on site of lesion(s):
    • Terminal hematuria: 
      • Blood noted near or at the end of voiding
      • Generally comes from the bladder neck or prostatic urethra
    • Blood in the beginning of urination: typically from the urethra
    • Hematuria throughout urination: can be from the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys, ureter, and/or bladder
  • Dysuria 
  • Urinary frequency
  • Urge incontinence 
  • Back pain Back pain Back pain is a common complaint among the general population and is mostly self-limiting. Back pain can be classified as acute, subacute, or chronic depending on the duration of symptoms. The wide variety of potential etiologies include degenerative, mechanical, malignant, infectious, rheumatologic, and extraspinal causes. Back Pain
  • Flank pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain 
  • Suprapubic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain 
  • Fatigue 
  • Unexplained significant weight loss

Diagnosis

  • History and physical examination:
    • Solid pelvic mass on abdominal examination Abdominal examination The abdominal examination is the portion of the physical exam evaluating the abdomen for signs of disease. The abdominal examination consists of inspection, auscultation, percussion, and palpation. Abdominal Examination (late sign)
    • Enlarged lymph nodes on examination
    • History of chronic bladder irritation
  • Urinalysis: 
    • Indicated for any presentation of hematuria: considered significant if > 3 RBCs per high-power field (HPF)
    • RBC morphology:
      • Dysmorphic or formed in casts (cylindrical or tubular particles): likely intrinsic renal disease
      • Normally shaped RBCs: infection, tumor, calculi, or obstruction
  • Urine cytology:
    • A urine sample is collected and observed under a microscope to detect cancer cells. 
    • Has poor sensitivity 
  • Cystoscopy + biopsy:
    • Gold standard for initial diagnosis and staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis of bladder cancer 
    • Visible tumors or suspicious lesions are biopsied or resected transurethrally. 
    • Fluorescence cystoscopy: photoactive protoporphyrin accumulates in the neoplastic tissue.  
  • Urine-based tumor markers:
    • A noninvasive diagnostic tool
    • Based on expressed tumor-related proteins, DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure, RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure, methylation changes, or cellular markers
    • More sensitive than urine cytology, but not sensitive enough to replace cystoscopy
  • Imaging: 
    • CT (with and without contrast)
      • Preferred method of imaging for all stages 
      • Both abdominal and pelvic scans are taken. 
    • Intravenous pyelography (IVP):
      • Can visualize both the bladder and the upper urinary tracts 
      • Ideal choice for evaluating microscopic or gross hematuria or for those with suspected urothelial cancer
      • Sensitive in detecting small lesions of the ureter or renal pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis 
      • With use of radiocontrast agents, IVP should be avoided in cases of renal insufficiency or allergy to contrast.
    • MRI:  
      • Gadolinium-enhanced MRI is more sensitive than CT in cases of multiple tumors and in determining tumor extension and invasion.
      • Better for evaluating tumors at the base and dome of the bladder 
      • Cannot be used in those with claustrophobia, pacemakers, or metallic foreign bodies
    • Ultrasonography: 
      • Not used to confirm the diagnosis or to stage bladder cancer 
      • Able to detect the presence of a soft tissue mass, but the extent of invasion cannot be determined 
  • For metastasis screening:
    • Chest x-ray: sensitive for lesions ≥ 1 cm 
    • CT is more sensitive than chest x-ray. 
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones scan: 
      • Used to detect bone metastases 
      • Recommended in cases with elevated alkaline phosphatase

Stages of bladder cancer

Bladder cancer pathologic stages are based on the TNM staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis system.

Table: Primary tumor
Tumor (T)
category
Description
Tx Primary tumor cannot be assessed.
T0 No evidence of primary tumor
Ta Noninvasive papillary or exophytic lesions
Tis Carcinoma in situ (“flat tumor”)
T1 Tumor invades lamina propria (or submucosa).
T2 Tumor invades muscularis propria.
T2a: Tumor invades superficial muscularis propria (inner half).
T2b: Tumor invades deep muscularis propria (outer half).
T3 Tumor invades perivesical fat.
T3a: Microscopic invasion
T3b: Macroscopic (extravesical mass) invasion
T4 Tumor invades 1 of the following: prostatic stroma, seminal vesicles Seminal vesicles A saclike, glandular diverticulum on each ductus deferens in male vertebrates. It is united with the excretory duct and serves for temporary storage of semen. Prostate and other Male Reproductive Glands, uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Posterior Abdominal Wall, vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor, pelvic wall, abdominal wall.
T4a: Tumor invades prostatic stroma, uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Posterior Abdominal Wall, vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor (adjacent organs).
T4b: Tumor invades pelvic wall, abdominal wall, or other organs.
Table: Regional lymph nodes
Node (N) category Description
Nx Lymph nodes cannot be assessed.
N0 No lymph node metastasis
N1 Single regional lymph node metastasis in the true pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis (perivesical, obturator, internal and external iliac, or sacral lymph nodes)
N2 Multiple regional lymph node metastases in the true pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis (perivesical, obturator, internal and external iliac, or sacral lymph node metastasis)
N3 Metastasis to the common iliac lymph nodes
Table: Distant metastasis
Metastasis (M) category Description
M0 No distant metastasis
M1 Distant metastasis
M1a: distant metastasis limited to lymph nodes beyond the common iliac nodes
M1b: non–lymph node distant metastasis
Table: Stage/prognostic groups
Stage T N M
Stage 0a Ta N0 M0
Stage 0is Tis N0 M0
Stage I T1 N0 M0
Stage II T2a N0 M0
T2b N0 M0
Stage IIIA T3a, T3b, T4a N0 M0
Stage IIIA T1–T4a N1 M0
Stage IIIB T1–T4a N2, N3 M0
Stage IVA T4b Any N M0
Stage IVA Any T Any N M1a
Stage IVB Any T Any N M1b

Management

  • Lifestyle changes: 
    • Cessation of smoking
    • Increased intake of water 
    • Multivitamin supplementation 
    • Adequate exercise and dietary changes 
  • Treatment for bladder cancer depends on the stage of the tumor: 
    • Non–muscle invasive (Ta, T1, carcinoma in situ [CIS]):
  • Transurethral resection of bladder tumor
  • Potential adjuvant intravesical therapy to decrease risk of recurrence (dependent on risk)
  • Intravesical bacille Calmette-Guérin (BCG; live attenuated form of Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium bovis) is used for high-risk disease.
  • Other intravesical agents: gemcitabine, mitomycin, epirubicin
  • Muscle invasive disease (any lymph node status but no metastasis (M0)):
    • Radical cystectomy (requires urinary diversion): removes the bladder, adjacent organs (prostate, seminal vesicles Seminal vesicles A saclike, glandular diverticulum on each ductus deferens in male vertebrates. It is united with the excretory duct and serves for temporary storage of semen. Prostate and other Male Reproductive Glands, uterus Uterus The uterus, cervix, and fallopian tubes are part of the internal female reproductive system. The uterus has a thick wall made of smooth muscle (the myometrium) and an inner mucosal layer (the endometrium). The most inferior portion of the uterus is the cervix, which connects the uterine cavity to the vagina. Posterior Abdominal Wall, ovaries Ovaries Ovaries are the paired gonads of the female reproductive system that contain haploid gametes known as oocytes. The ovaries are located intraperitoneally in the pelvis, just posterior to the broad ligament, and are connected to the pelvic sidewall and to the uterus by ligaments. These organs function to secrete hormones (estrogen and progesterone) and to produce the female germ cells (oocytes). Ovaries) and regional lymph nodes
    • Neoadjuvant chemotherapy
    • Trimodal therapy (transurethral resection of bladder tumor, radiation, and chemotherapy): preserves the bladder for those who are not candidates for cystectomy
  • Metastasis present (M1):
    • Chemotherapy (platinum-based)
    • Checkpoint inhibitor immunotherapy targeting programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death-1 protein (PD-1) or its ligand (PD-L1)
    • Palliative care
  • Surveillance:
    • Second primary tumors can arise anywhere in the genitourinary tract.
    • Cystoscopy and urine cytology performed every 3 months in the 1st 2 years.
    • Frequency subsequently decreases.

Prognosis

  • The recurrence rate for urothelial carcinoma is high, with 80% of cases having ≥ 1 recurrence. 
  • The 5-year survival rate:
    • CIS/minimal muscle invasion (T1): 82%–100%
    • Muscle invasion (T3 onward): up to 71%
    • T4: up to 22%
  • Risk factors for recurrence and progression are: 
    • Female sex
    • Large tumor size
    • Multifocality 
    • Advanced stage 
    • Presence of CIS

Ureteral Cancer

Definition

Abnormal growth of cells in the inner lining of the ureter/ureters, of which > 90% are urothelial carcinomas.

Clinical presentation

  • Ureteral cancer is usually asymptomatic in the initial stages, with clinical presentation as follows:
    • Painless gross hematuria (throughout micturition)
    • Flank pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Unexplained weight loss 
    • Fatigue
  • On presentation, up to 17% have bladder cancer as well.
  • Because the entire urothelial surface is exposed to carcinogenic alteration (field cancerization), multifocality can be seen.

Diagnosis

  • History and physical examination: 
    • Presenting signs and symptoms
    • Exposure history
    • History of cancer or genetic predisposition 
    • Generally, exam is unremarkable, but in rare cases, a flank mass may be found. 
  • Urinalysis: evaluate hematuria
  • Urine cytology:
    • Generally negative in low-grade urothelial cancers of the upper tract
    • ↑ Chance of positive cytology in higher-grade lesions
    • Positive cytology + negative cystoscopy/biopsy → must evaluate the upper tracts and prostatic urethra
  • Radiologic imaging:
    • Imaging is used to identify the tumor (usually seen as a filling defect) and to assess the extent of the cancer.
    • CT urography provides better visualization than IVP. 
    • MRI is an alternative (but gadolinium is contraindicated in impaired renal function, which carries the risk of development of nephrogenic systemic fibrosis).
  • Ureteropyeloscopy with cystoscopy: 
    • Visualization of the entire collecting system with a camera
    • The scope passes the urethra and bladder into the ureters. 
    • Biopsy of the mass can be taken.
Ureteral tumor

Ureteral tumor noted on endoscopic examination of the ureter.

Image: “Ureteral tumour with elective indication for endoscopic treatment” by Niţă G, Georgescu D, Mulţescu R, Draguţescu M, Mihai B, Geavlete B, Persu C, Geavlete P. License: CC BY 2.0

Stages of ureteral cancer

Staging applies to cancer involving the renal pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis and ureter.

Table: Primary tumor
T category Description
TX Primary tumor cannot be assessed.
T0 No evidence of primary tumor
Ta Noninvasive papillary or exophytic lesions
Tis CIS
T1 Tumor invasion of subepithelial connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue
T2 Tumor invasion of muscularis
T3 For ureter only: invasion beyond muscularis into periureteric fat. For renal pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis only: invasion beyond muscularis into peripelvic fat or into the renal parenchyma
T4 Tumor invasion of adjacent organs or the kidney into the perinephric fat
Table: Regional lymph nodes
Node category Description
NX Regional lymph nodes cannot be assessed.
N0 No lymph node metastasis
N1 Metastasis ≤ 2 cm (single lymph node)
N2 Metastasis > 2 cm (single lymph node or multiple lymph nodes)
Table: Metastasis
M category Description
M0 No distant metastasis
M1 Distant metastasis
Table: Stage/prognostic groups
Stage T N M
Stage 0a Ta N0 M0
Stage 0is Tis N0 M0
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
Stage IV T4 NX, N0 M0
Any T N1, N2 M0
Any T Any N M1

Management

Treatment of ureteral cancer depends on the site, size, and extent of cancer, with surgery providing curative treatment. 

  • Localized disease:
    • Nephroureterectomy (laparoscopic or open)
      • Removal of the ureter and kidney reduces risk of local recurrence.
      • Surgery includes excision of the cuff of the bladder and bladder mucosa.
      • Lymph node dissection is performed in high-grade lesions.
    • Kidney-sparing surgery:
      • Considered in low-risk lesions
      • Also a consideration in solitary kidney or impaired renal function
    • Chemotherapy:
      • Adjuvant treatment given with muscle invasion
      • Gemcitabine + platinum-based chemotherapy
      • Intravesical treatment (pirarubicin or mitomycin) decreases bladder recurrence.
  • Advanced disease: 
    • Chemotherapy
    • Checkpoint inhibitor immunotherapy
Nephroureterectomy in ureteral cancer

Nephroureterectomy in ureteral cancer

Image: “Nephroureterectomy (with endoscopic desinsertion) for ureteral tumours” by Niţă G, Georgescu D, Mulţescu R, Draguţescu M, Mihai B, Geavlete B, Persu C, Geavlete P. License: CC BY 2.0

Prognosis

  • The 5-year survival rate for ureteral cancer overall is 71%, with prognosis worsening with advancing stage. 
  • Upper urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract urothelial cancer has a risk of recurrence in the bladder (seen in about 44%).
    • With recurrence, bladder lesions are usually multifocal.
    • Surveillance includes cystoscopy every 6 months for many years, with imaging added depending on the risk factors and findings.

Urethral Cancer

Definition

Urethral cancer is an extremely rare malignancy (< 1% of all genitourinary malignancies) that involves the abnormal growth of cells in the lining of the urethra.

Clinical presentation

Urethral cancer has an insidious onset and can remain asymptomatic for a long time. Symptoms vary between men and women:

  • Men:
    • Often nonspecific, which contributes to the delay in diagnosis
    • Up to 30% have lymph node metastasis at the time of presentation.
    • Among the presenting features:
      • Hematuria (initial hematuria more often than terminal hematuria)
      • Difficulty voiding
      • Dysuria
      • Urethral discharge (purulent, foul-smelling, or watery discharge)
      • Urinary retention (in advanced disease)
      • Perineal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
      • Genital swelling
      • Priapism
  • Women:
    • Hematuria
    • Irritating voiding symptoms
    • Pelvic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Dyspareunia

Diagnosis

  • History and physical examination 
    • History of: 
      • Recurrent urethral infections
      • Urethral stricture 
      • STIs 
    • Physical examination for urethral lesions and lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
    • Bimanual exam in women
  • Cystourethroscopy: 
    • A cystoscope is used to view the urethra and the bladder.
    • A tissue biopsy is taken, if necessary. 
    • Views the extent of spread of the cancer 
  • Imaging: 
    • CT or MRI
    • MRI is sensitive and shows the location, size, and spread of the tumor. 
    • Imaging should include the chest to check for metastasis.
    • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones scan is added if with elevated alkaline phosphatase, related symptoms, or imaging findings.
Papillary tumor

Video urethrocystoscopy showing a papillary tumor in the bulbar urethra

Image: “Video urethrocystoscopy showing papillary tumor at the level of bulbar urethra.” by Journal of Endourology Case Reports. License: CC BY 4.0

Staging

Urethral cancer is staged according to the TNM criteria.

Table: Primary tumor (female urethra and male penile urethra)
T category Description
Tx Primary tumor cannot be assessed.
T0 No evidence of primary tumor
Ta Noninvasive papillary carcinoma
Tis Carcinoma in situ
T1 Tumor invasion of subepithelial connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue
T2 Tumor invasion of the corpus spongiosum or periurethral muscle
T3 Tumor invasion of the corpus cavernosum or anterior vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor
T4 Tumor invasion of other adjacent organs
Table: Primary tumor (prostatic urethra)
T category Description
Tx Primary tumor cannot be assessed.
T0 No evidence of primary tumor
Ta Noninvasive papillary carcinoma
Tis Carcinoma in situ (involves the prostatic urethra or periurethral or prostatic ducts without stromal invasion)
T1 Tumor invasion of the subepithelial connective tissue Connective tissue Connective tissues originate from embryonic mesenchyme and are present throughout the body except inside the brain and spinal cord. The main function of connective tissues is to provide structural support to organs. Connective tissues consist of cells and an extracellular matrix. Connective Tissue immediately underlying the urothelium
T2 Tumor invasion of the prostatic stroma surrounding ducts (by directly extending from the urothelial surface or by invading from prostatic ducts)
T3 Tumor invasion of the periprostatic fat
T4 Tumor invasion of the adjacent organs
Table: Regional lymph nodes
N category Description
Nx Regional lymph nodes cannot be assessed.
N0 Regional lymph node metastasis is not present.
N1 Single regional lymph node metastasis in the inguinal region or true pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis or presacral lymph node
N2 Multiple lymph node metastases in the inguinal region or true pelvis Pelvis The pelvis consists of the bony pelvic girdle, the muscular and ligamentous pelvic floor, and the pelvic cavity, which contains viscera, vessels, and multiple nerves and muscles. The pelvic girdle, composed of 2 "hip" bones and the sacrum, is a ring-like bony structure of the axial skeleton that links the vertebral column with the lower extremities. Pelvis or presacral lymph node
Table: Distant metastasis
M category Description
M0 No distant metastasis
M1 Distant metastasis
Table: Staging of urethral cancer
Stage T N M
Stage 0a Ta N0 M0
Stage 0is Tis N0 M0
Stage I T1 N0 M0
Stage II T2 M0
Stage III T1, T2 N1 M0
T3 N0, N1 M0
Stage IV T4 N0, N1 M0
Any T N2 M0
Any T Any N M1

Management

Localized disease (up to T2) is generally treated with surgery, while locally advanced conditions are treated with multimodal therapy.

  • In men, the surgical options for urethral cancer are: 
    • Low-grade or small high-grade noninvasive tumors: endoscopic resection
    • High-grade, noninvasive tumors: segmental resection
    • Distal tumors: distal urethrectomy, creating hypospadias
    • More extensive tumors (T2): subtotal urethrectomy
    • Urothelial carcinoma invading the prostatic stroma: neoadjuvant chemotherapy, radical cystoprostatectomy with urinary diversion 
    • More advanced disease (T3 or T4) requires extensive surgical resection (urethra, prostate, bladder with penectomy).
  • In women:
    • Low-grade or small high-grade noninvasive tumors: endoscopic resection
    • Extensive disease: urethrectomy, bladder neck closure, and urinary diversion
    • Advanced disease (T3 or T4): neoadjuvant chemotherapy with extensive surgical resection (urethra, anterior vagina Vagina The vagina is the female genital canal, extending from the vulva externally to the cervix uteri internally. The structures have sexual, reproductive, and urinary functions and a rich blood supply, mainly arising from the internal iliac artery. Vagina, Vulva, and Pelvic Floor, bladder with possible pubectomy)
  • Chemotherapy:
    • Regimen differs by histology 
    • Urothelial carcinoma can be treated with:
      • Cisplatin, gemcitabine, ifosfamide (CGI)
      • Ifosfamide, paclitaxel, cisplatin
      • Methotrexate, vinblastine, doxorubicin, cisplatin
  • Radiation therapy: 
    • Used alone (localized tumors) or coupled with chemotherapy especially in those who are not candidates for surgery
    • May be used for palliation 
    • Side effects: 
      • Bladder pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain 
      • Incontinence
      • Bleeding 
      • Rectal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain 
      • Rectal bleeding
      • Vaginal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and/or bleeding, in women 
      • Narrowing of the urethra 
  • Posttreatment:
    • Follow-up visits are generally every 3–4 months for 1st 2 years and then twice a year. 
    • Physical examination (check inguinal lymph nodes)
    • Endoscopy to check remaining urethra
    • Imaging

Prognosis

  • Nodal stage is an important predictor of survival.
  • Recurrence of urethral cancer is lower at early stages.
  • Urethral cancer generally has a 32% survival rate at 10 years.

Differential Diagnosis

The following differential diagnoses are for an individual presenting with hematuria:

  • IgA nephropathy IgA nephropathy IgA nephropathy (Berger's disease) is a renal disease characterized by IgA deposition in the mesangium. It is the most common cause of primary glomerulonephritis in most developed countries. Patients frequently present in the second and third decades of life and, historically, with a preceding upper respiratory or GI infection. IgA Nephropathy: also known as Berger disease. IgA nephropathy IgA nephropathy IgA nephropathy (Berger's disease) is a renal disease characterized by IgA deposition in the mesangium. It is the most common cause of primary glomerulonephritis in most developed countries. Patients frequently present in the second and third decades of life and, historically, with a preceding upper respiratory or GI infection. IgA Nephropathy is a renal disease characterized by IgA deposition in the mesangium. Presentation usually is associated with a preceding upper respiratory or GI infection. Common presenting features are gross hematuria or asymptomatic, microscopic hematuria on urinalysis. The course is often benign, with renal biopsy performed only in cases of severe, progressive renal disease. Treatment depends on the severity of proteinuria, renal function, and pathologic changes. ACEis or ARBs are given to reduce disease progression. Immunosuppressive therapy given in more severe conditions.  
  • Alport syndrome Alport Syndrome Alport syndrome, also called hereditary nephritis, is a genetic disorder caused by a mutation in the genes encoding for the alpha chains of type IV collagen, resulting in the production of abnormal type IV collagen strands. Patients present with glomerulonephritis, hypertension, edema, hematuria, and proteinuria, as well as with ocular and auditory findings. Alport Syndrome: also called hereditary nephritis. Alport syndrome Alport Syndrome Alport syndrome, also called hereditary nephritis, is a genetic disorder caused by a mutation in the genes encoding for the alpha chains of type IV collagen, resulting in the production of abnormal type IV collagen strands. Patients present with glomerulonephritis, hypertension, edema, hematuria, and proteinuria, as well as with ocular and auditory findings. Alport Syndrome is a genetic disorder caused by a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the genes encoding for the alpha chains of type IV collagen, resulting in the production of abnormal type IV collagen strands. Presenting features include glomerulonephritis, hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, hematuria, and proteinuria, as well as ocular (cataract, retinopathy) and auditory (sensorineural hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss) findings. Diagnosis is established with laboratory tests, and a renal biopsy showing characteristic glomerular basement membrane splitting may be used to confirm diagnosis. Treatment for Alport syndrome Alport Syndrome Alport syndrome, also called hereditary nephritis, is a genetic disorder caused by a mutation in the genes encoding for the alpha chains of type IV collagen, resulting in the production of abnormal type IV collagen strands. Patients present with glomerulonephritis, hypertension, edema, hematuria, and proteinuria, as well as with ocular and auditory findings. Alport Syndrome is focused on limiting disease progression with ARBs and ACEis. Hearing aids AIDS Chronic HIV infection and depletion of CD4 cells eventually results in acquired immunodeficiency syndrome (AIDS), which can be diagnosed by the presence of certain opportunistic diseases called AIDS-defining conditions. These conditions include a wide spectrum of bacterial, viral, fungal, and parasitic infections as well as several malignancies and generalized conditions. HIV Infection and AIDS are used for hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss associated with Alport syndrome Alport Syndrome Alport syndrome, also called hereditary nephritis, is a genetic disorder caused by a mutation in the genes encoding for the alpha chains of type IV collagen, resulting in the production of abnormal type IV collagen strands. Patients present with glomerulonephritis, hypertension, edema, hematuria, and proteinuria, as well as with ocular and auditory findings. Alport Syndrome
  • Poststreptococcal glomerulonephritis Poststreptococcal Glomerulonephritis Post-streptococcal glomerulonephritis (PSGN) is a type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus (GAS). The clinical presentation of PSGN can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome, which is characterized by red-to-brown urine, proteinuria, edema, and acute kidney injury. Poststreptococcal Glomerulonephritis ( PSGN PSGN Post-streptococcal glomerulonephritis (PSGN) is a type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus (GAS). The clinical presentation of PSGN can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome, which is characterized by red-to-brown urine, proteinuria, edema, and acute kidney injury. Poststreptococcal Glomerulonephritis): type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus (GAS). The clinical presentation of PSGN PSGN Post-streptococcal glomerulonephritis (PSGN) is a type of nephritis that is caused by a prior infection with group A beta-hemolytic Streptococcus (GAS). The clinical presentation of PSGN can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome, which is characterized by red-to-brown urine, proteinuria, edema, and acute kidney injury. Poststreptococcal Glomerulonephritis can range from asymptomatic, microscopic hematuria to full-blown acute nephritic syndrome Nephritic syndrome Nephritic syndrome is a broad category of glomerular diseases characterized by glomerular hematuria, variable loss of renal function, and hypertension. These features are in contrast to those of nephrotic syndrome, which includes glomerular diseases characterized by severe proteinuria, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephritic Syndrome, which is characterized by red-to-brown urine, proteinuria, edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema, and AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury. The diagnosis is made on the basis of clinical findings in the setting of recent GAS infection. Management is supportive and involves treating the clinical manifestations. The prognosis is generally favorable, especially in children.  
  • Nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis: hard mineral or salt deposits in the kidney that present with severe pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain in the renal angle, proteinuria, nausea, and vomiting, increased urinary frequency, and pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain that radiates to the lower abdomen and groin. Diagnosis is by imaging, and management is with administration of analgesics and surgery to remove the stones.

References

  1. Babaian, K., Adams, P., McClure, C., Tompkins, B., McMurray, M. (2021). Bladder cancer. Medscape. Retrieved November 30, 2021, from https://emedicine.medscape.com/article/438262-overview
  2. Daneshmand, S. (2021). Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder. UpToDate. Retrieved November 22, 2021 from https://www.uptodate.com/contents/epidemiology-and-risk-factors-of-urothelial-transitional-cell-carcinoma-of-the-bladder
  3. Daneshmand, S., Efstathiou, J. (2021). Urethral cancer. UpToDate. Retrieved November 22, 2021, from https://www.uptodate.com/contents/urethral-cancer
  4. Hahn, N.M. (2018). Cancer of the bladder and urinary tract. Chapter 82 of Jameson J., Fauci A.S., Kasper D.L., Hauser S.L., Longo D.L., Loscalzo J (Eds.),  Harrison’s Principles of Internal Medicine, 20th ed. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192016282
  5. Lerner, S.  (2021). Overview of the initial approach and management of urothelial bladder cancer. UpToDate. Retrieved on November 2, 2021, from https://www.uptodate.com/contents/overview-of-the-initial-approach-and-management-of-urothelial-bladder-cancer
  6. Lotan, Y., Choueiri, T. (2021). Clinical presentation, diagnosis and staging of bladder cancer. UpToDate. Retrieved November 22, 2021, from https://www.uptodate.com/contents/clinical-presentation-diagnosis-and-staging-of-bladder-cancer
  7. Shariat, S., Laukhtina, E., Pradere, B. (2021). Urethral cancer. Medscape. Retrieved November 30, 2021, from https://emedicine.medscape.com/article/451496-overview#:~:text=Primary%20urethral%20cancer%20(PUC)%20is,for%20men%20and%20African%20Americans.
  8. Steinberg, G., DeCastro, J., Patel, A. (2020). Bladder cancer staging. Medscape. Retrieved November 30, 2021, fromhttps://emedicine.medscape.com/article/2006834-overview

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