Christopher Wright, MD
Mark L. Jordan, MD, FACS
BASICS
DESCRIPTION
• Heterogeneous group of disorders with extracellular deposition of protein in abnormal fibrillar form:
– Can involve any organ system
– Kidney, ureters, seminal vesicles, prostate, penis, and testis can be involved
– >50% of genitourinary (GU) tract cases involve the bladder
– Commonly forms “pseudotumors” in bladder, ureter, or renal pelvis
• 25 structurally unrelated proteins known to cause amyloidosis
• May be primary, secondary, or hereditary
• May be organ limited or systemic
EPIDEMIOLOGY
Incidence
• Uncommon disorder and exact worldwide incidence is unknown
– In the United States appears to be stable at 6–10 cases per million person-years
• Age-specific incidence rates increase in each decade over age 40
– Median age at diagnosis is 64 yr and <5% of patients are under age 40 (1)
RISK FACTORS
• Chronic and recurrent mucosal and submucosal inflammation
• Hemodialysis patients develop deposits in kidneys
• Chronic inflammatory disorders
Genetics
• Familial or hereditary amyloidosis exists
• Dozens of specific variations described
• Familial forms often do not present until adulthood
• Patients with immunoglobulin light chain (AL) amyloidosis frequently have chromosomal abnormalities but there is no single chromosome change that is diagnostic
PATHOPHYSIOLOGY
• More than 20 distinct low–molecular-weight proteins are recognized to form amyloid fibrils, the 2 most common being (2):
– AL, formerly referred to as primary amyloidosis
Fibrils composed of fragments of monoclonal light chains
Affected patients may have amyloidosis alone or in association with other plasma cell dyscrasias (eg, multiple myeloma)
– AA amyloidosis
Fibrils composed of fragments of the acute phase reactant serum amyloid A
Typically reactive (secondary) to chronic inflammation
• Thought to be a misfolding event; misfolded variants are prone to self-aggregation
– These become insoluble complexes that accumulate in tissues
• Renal amyloid is often a glomerular deposition leading to proteinuria
ASSOCIATED CONDITIONS
• End-stage renal disease (ESRD) requiring dialysis
• Nephrotic syndrome
• Diabetes
• Multiple myeloma
• Familial Mediterranean fever (FMF)
– Hereditary inflammatory disorder characterized by severe attacks of abdominal pain in 95% of patients
– AA amyloidosis with renal failure is common complication
GENERAL PREVENTION
N/A
DIAGNOSIS
• Clinical presentation depends on the number and nature of the organs affected
• Even in patients with multiple-organ involvement, it is usually possible to identify 1 organ as the “dominant” site of involvement
HISTORY
• Nonspecific symptoms such as fatigue and weight loss are common
• Patient on dialysis
• Family history of amyloidosis
• Chronic disease or inflammation
• Cardiac:
– 60% of patients
– Signs/symptoms of heart failure
• Neurologic:
– 20% with mixed sensory and peripheral neuropathy
– Carpal tunnel syndrome
• Liver:
– 70% will have hepatomegaly
• Bladder:
– Painless hematuria in 75%
– Irritative symptoms (urgency, frequency)
– Clinically similar to bladder cancer
• Ureter:
– Flank pain if obstruction
– Anuria if bilateral amyloidosis
– Hematuria
• Prostate:
– Hematuria
– Bladder outlet obstruction may be present
PHYSICAL EXAM
• Peripheral edema (nephritic syndrome)
• Hepatosplenomegaly
• Generally no specific physical exam findings
DIAGNOSTIC TESTS & INTERPRETATION
• Proteinuria in 50–80%
• Renal failure in 50%
• Elevated liver function tests (cholestatic pattern)
• Diagnosis of AL amyloidosis requires evidence of a monoclonal proliferative disorder
– Serum or urine monoclonal (M) protein can be detected
Imaging
• CT or ultrasound (US) may demonstrate hydronephrosis secondary to obstruction (ureteral amyloid)
• Magnetic resonance imaging (MRI):
– T2-weighted images are suggestive of amyloid deposition. Can be confused with prostate cancer invading into seminal vesicles on MRI for prostate
Diagnostic Procedures/Surgery
• Cystoscopy for hematuria
– Lesions are difficult to distinguish from transitional cell carcinoma (TCC) without biopsy or resection
• Ureteroscopy or retrograde pyelogram for ureteral involvement
• Biopsy
– Abdominal fat pad aspirate or bone marrow biopsy have high success rates and are preferred sites of biopsy
– Renal biopsy performed if former is negative with high suspicion
Will be positive in >90% of cases
Pathologic Findings
• Diagnosis requires histologic demonstration of amyloid deposits:
– Congo red stain
Orange under light microscope
Green birefringence under polarized light
– Electron microscopy can be used to identify microfibrils
– Immunohistochemical analysis assists in typing:
Diagnosis of transthyretin-type amyloidosis limits need for further evaluation as it identifies the amyloidosis as inherited
• Seminal vesicle amyloidosis can be seen in radical prostatectomy specimens but the significance is unknown
DIFFERENTIAL DIAGNOSIS
• Bladder
– Difficult to distinguish from TCC without biopsy
• Ureter
– May be confused with stones or other causes of obstruction (eg, strictures)
• Nephrotic syndrome and glomerulonephritis
TREATMENT
GENERAL MEASURES
• In AL amyloidosis treatment is aimed at reducing the production of monoclonal light chain precursor with chemotherapy or, occasional, radiotherapy or surgery of a localized amyloidogenic plasmacytoma
• In AA amyloidosis treatment is generally supportive with therapy directed at primary cause if identified
MEDICATION
First Line
• High-dose melphalan chemotherapy followed by autologous blood stem cell transplantation (2)
– 25–67% complete hematologic response seen in single and multicenter trials
– Response far exceeds cyclic oral melphalan and prednisone (see 2nd line)
• Colchicine can be used in FMF to prevent proteinuria
Second Line
• Low-dose oral melphalan with prednisone in a cyclical fashion
– Rarely results in complete hematologic response or reversal of amyloid-related organ dysfunction
SURGERY/OTHER PROCEDURES
• Renal transplant
– Graft survival similar to matched controls without amyloidosis
– Recurs in graft in 20–33% due to continued activity of underlying disease
• TUR of bladder lesion with fulguration
– Adjuvant intravesical DMSO has shown success in preventing recurrence (3)
ADDITIONAL TREATMENT
Radiation Therapy
Only rarely used for localized amyloidogenic plasmacytoma
Additional Therapies
• Supportive care
– Management of heart failure
– Salt restriction, diuretics, and treatment of secondary hyperlipidemia for nephrotic syndrome
– Analgesics for neuropathic pain
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Single institution experience of 421 patients who received high-dose melphalan with stem cell transplant shows event-free survival and overall survival of 2.6 and 6.3 yr, respectively (4)
• Long-term survival in those who develop renal failure remains poor
– Ranges from 12–24 mo
• AA amyloidosis has better prognosis
COMPLICATIONS
See above
FOLLOW-UP
Patient Monitoring
• Bladder or urethra
– Repeat periodic surveillance cystoscopies
– Recurrence rates >50%
• Ureters
– US or CT to monitor hydronephrosis
Patient Resources
Amyloidosis foundation (www.amyloidosis.org)
REFERENCES
1. Kyle RA, Linos A, Beard CM, et al. Incidence and natural history of primary systemic amyloidosis in Olmsted County, Minnesota, 1950 through 1989 [see comments]. Blood. 1992;79:1817–1822.
2. Sanchorawala V, Jacobson DR, Seldin JC, Buxbaum JN. The Amyloidoses. In: Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT, eds. Williams Hematology, 8th ed. New York, NY: McGraw-Hill; 2010.
3. McCammon KA, Lentzner AN, Moriarty RP, et al. Intravesical dimethyl sulfoxide for primary amyloidosis of the bladder. Urology. 1998;52:1136–1138.
4. Cibeira MT, Sanchorawala V, Seldin DC, et al. Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: Long-term results in a series of 421 patients. Blood.2011;118:4346–4352.
ADDITIONAL READING
• Javed A, Canales BK, Maclennan GT. Bladder amyloidosis. J Urol. 2010;183:2388–2389.
• Mangera A, Linton KD, Fernando M, et al. What is the evidence for the management of urethral amyloidosis? A systematic review of the literature. BJU Int. 2012;109:1858–1861.
See Also (Topic, Algorithm, Media)
• Amyloidosis Image 
• Bladder Tumors, Benign and Malignant, General Considerations
• Bladder Mass, Differential Diagnosis
• Filling Defect, Upper Urinary Tract (Renal Pelvis and Ureter)
CODES
ICD9
• 277.30 Amyloidosis, unspecified
• 277.39 Other amyloidosis
• 583.81 Nephritis and nephropathy, not specified as acute or chronic, in diseases classified elsewhere
ICD10
• E85.3 Secondary systemic amyloidosis
• E85.8 Other amyloidosis
• N08 Glomerular disorders in diseases classified elsewhere
CLINICAL/SURGICAL PEARLS
• Both surgically and radiologically, genitourinary amyloidosis may mimic TCC in GU tract, therefore biopsy is needed.
• Abdominal fat pad aspirate is preferred location to obtain biopsy, followed by bone marrow and finally kidney.