Primary Amyloidosis Of The Genitourinary Tract

for more information:ali.ma@wecistanche.com

Khaleel I. Al-Obaidy, MD; David J. Grignon, MD†

Amyloidosis is a heterogeneous group of disorders caused by the deposition of misfolded proteins in the extracellular tissues.1 These misfolded proteins are formed of different amino acid peptides that share a common backbone of b-sheet conformation. This renders them insoluble and resistant to proteolytic activity.^2,3 Based on the amino acid composition, the form of the amyloid deposit varies in severity and organ involvement. To date, more than 25 proteins have been described to be amyloidogenic, all of which are indistinguishable by light or electron microscopic examination.^4,5

The etiology of localized amyloidosis is unknown. It has been postulated that recurrent chronic inflammation with associated migration of lymphoplasmacytic cells may result in an aberrant monoclonal proliferation and local secretion of light chains. These light chains may then accumulate and transform into amyloid by lysosomal degradation.¹¹ This review will highlight the clinical presentations and pathologic findings related to primary amyloidosis in each organ of the urinary tract system. This will also include highlights of unusual associations based on our institutional experience.

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DIAGNOSIS OF AMYLOIDOSIS

Radiologically, there is no specific finding to detect amyloidosis; however, some radiologic reports indicate that amyloidosis should be suspected when the lesion is visualized as a hypointensity on T2-weighted magnetic resonance images and no obvious mass is appreciated, whereas others consider the presence of calcifications as a typical computed tomography scan sign of amyloidosis, despite it being nonspecific and appearing in many other conditions.^12,13

The definitive diagnosis of amyloidosis requires histologic examination. Microscopically, amyloidosis deposits in the tissue as an extracellular pink, homogenous, amorphous, and acellular material. Although its appearance may suggest the diagnosis, the presence of amyloidosis requires confirmatory testing by special histochemical stains. Congo red stain, which typically renders amyloid deposits a salmonpink color, is the most commonly used stain for its detection. Despite this characteristic appearance of Congo red stain, it has to be examined under polarized light, which shows apple-green birefringent deposits.14 All amyloid types can be detected by Congo red stain; however, the secondary (amyloid A) type loses the affinity to stain for Congo red when it is pretreated with potassium permanganate.15,16 Amyloid detection can also be achieved using immunohistochemical methods. However, this may as well reveal inconclusive results related to epitopic characteristics or background staining.

Despite this relatively straightforward diagnosis of amyloidosis, additional subtyping is required for treatment. This subtyping is achieved by laser microdissection, then analysis by liquid chromatography/mass spectrometry technology. This methodology has its value in confirming the diagnosis as well as subtyping based on the peptide composition of the amyloidogenic protein with high sensitivity and specifificity.¹⁷

PRIMARY AMYLOIDOSIS OF THE KIDNEY

The kidney is the most frequently involved organ in the genitourinary tract system. The estimated prevalence of renal amyloidosis is 2% to 3% in renal biopsies, most commonly of amyloid light-chain or amyloid A types.5,18 When symptomatic, patients present with a variable degree of proteinuria, ranging from subnephrotic to massive proteinuria, along with other features of nephrotic syndrome. The severity of symptoms depends on multiple factors, including the intrarenal distribution of the deposits. For instance, amyloid light-chain amyloidosis most commonly has a glomerular deposit and presents with proteinuria in up to 75% of patients, whereas amyloid A is commonly reported in crescentic glomerulonephritis. Imaging is nonspecific and may show normal or enlarged kidneys.^19–23 To date, a single case of primary localized (amyloid light-chain) renal amyloidosis has been reported by Fuah and Lim24 in a 53-year-old male patient who presented with proteinuria.

Microscopically, amyloid deposition can be glomerular, interstitial, tubular, or vascular, with or without associated renal lesions.²⁵ In a proposed classification by Sxen and Sarsık,²⁶ renal amyloidoses were classified into 7 histomorphologic classes (0–VI), including no amyloid deposition, minimal (,10%) focal or segmental deposition in the mesangium or vascular pole, mesangial minimal (10%– 25%), focal mesangial capillary amyloid deposition (26%– 50%), diffuse mesangiocapillary deposition (51%–75%), membranous amyloid deposition, and advanced amyloidosis.

Despite attempts to unify the histomorphologic classification, the relationship between the degree and pattern of renal pathologic involvement and clinical outcome is still unclear. Slowly progressive chronic kidney disease is seen in patients with vascular and tubular amyloidosis. However, by far, glomerular deposit appears to be the most important factor determining the clinical outcome, especially when proteinuria is accompanied by other features of nephrotic syndrome.25,27 Additionally, intratubular amyloid precipitation (amyloid cast) has recently been described as a risk factor for systemic light-chain amyloidosis and may result in acute kidney injury.^5,22

PRIMARY AMYLOIDOSIS OF THE URETER

In the ureter, amyloidosis is rare and mostly published as case reports.²⁸ It occurs predominantly in females, with a female to male ratio of 1.9:1. The mean age at diagnosis is 58 years (range, 17–81 years), and the majority of patients present with flank pain, followed by hematuria.13 In a report by Ding et al,28 up to 60% of ureteric involvement was seen in the lower ureter, followed by the upper portion.

An unusual association between localized ureteric amyloidosis and nephrogenic adenoma was noted in one of the lesions identified in our institution. The ureteric lumen was circumferentially narrowed by an acellular hyaline material, admixed with numerous variably sized (PAX-8 positive) tubules in a background of abundant lymphoplasmacytic inflflammation. The acellular hyaline material had a salmon-pink color on Congo red stain and showed apple-green birefringence on polarization (Figures 1, A through D, and 2, A and B). This had formed a polypoid mass that further obstructed the ureteral lumen. It is unclear which lesion antecedes the other, but the chronic and recurrent inflflammation may have led to localized amyloidosis with subsequent trapping of renal tubular cells and the development of nephrogenic adenoma, further complicating the ureteric obstruction.

PRIMARY AMYLOIDOSIS OF THE URINARY BLADDER

Primary localized amyloidosis within the urinary bladder occurs commonly in older men (mean age, 55 years), and most patients present with gross hematuria, urinary irritation, or urinary obstructive symptoms.29,30 It mostly involves the posterior wall, followed by the dome of the bladder, in either single or multiple distributions.²⁹ The bladder may appear normal on cystoscopic examination, may show multiple edematous areas or may show a solid lesion. Additionally, it is not uncommon for localized amyloidosis to present as a neoplastic process with a mass effect mimicking malignancy.^31–34 Imaging characteristics are also non-specific and may show a mass lesion, thickening of the bladder wall, or areas of calcifications.34,35 This presentation may lead to transurethral resection of the bladder. Microscopically, amyloidosis is seen in the lamina propria as an abundant hyalinized, acellular extracellular material. The surface urothelium is benign and may show reactive changes. A Congo red histochemical stain should show salmon-pink color and give an apple-green birefringence on polarization.

Fibromyxoid nephrogenic adenoma is a benign lesion that should be considered in the differential diagnosis of amyloidosis, especially in the urinary bladder. It appears as compressed tubules and spindled cells in a prominent fifibromyxoid eosinophilic extracellular matrix.³⁶ In these cases, PAX-8 immunostain is helpful to establish the diagnosis.³⁷ Plasmacytoid urothelial carcinoma may also have a similar cystoscopic appearance to amyloidosis. The mucosa in this lesion may appear normal or edematous with no surface lesions. Histologically, the tumor cells are discohesive, have a plasmacytoid appearance, and are seen infiltrating into an edematous and myxoid stroma. An associated high-grade urothelial carcinoma component is usually seen in these cases.³⁸

Primary amyloidosis of the urinary bladder has a high recurrence rate, reaching 54% as reported by Tirzaman et al,²⁹ although many patients may remain free of recurrence for an extended period of time.

PRIMARY AMYLOIDOSIS OF THE PROSTATE AND SEMINAL VESICLES

Primary amyloidosis of the prostate is extremely rare, with fewer than 10 cases reported in the English-language literature. It was found in up to 1.5% of prostatectomies (n ¼ 4 of 262) as reported by Lupovitch.39 In the patients with predisposing systemic conditions such as multiple myeloma, Wilson et al40 reported that as many as 47% of prostates were involved by amyloidosis. The increasing trend toward prostatic biopsies is expected to affect this incidence over time, although no updated incidence reports are available. On examination, patients may present with prostatic nodularity and usually have increased serum prostate-specific antigen levels, most likely due to an associated inflflammation.^41,42 Microscopically, amyloid deposition is seen mostly in the stroma and sometimes around the blood vessels.⁴² More commonly, amyloidosis is seen to affect the seminal vesicles. This represents the second most common urinary organ to be involved by amyloidosis, after the kidneys. Amyloidosis of seminal vesicles and ejaculatory ducts is incidental in the vast majority of cases, and the diagnosis is made on prostatectomy specimens performed for prostatic adenocarcinoma. It is estimated that the seminal vesicle and ejaculatory ducts are involved by amyloidosis in up to 16% of autopsy series and 1.1% to 4.7% of resected prostatectomy specimens.^43–46

Imaging studies of seminal vesicles may show low-signal intensity mimicking neoplastic involvement by adenocarcinoma.^47,48 This may affect treatment decisions in patients with prostatic adenocarcinoma, as it can be interpreted as prostatic carcinoma extension into the seminal vesicles. Microscopically, amyloidosis often involves the seminal vesicles bilaterally, in a subepithelial distribution with variable luminal compression and narrowing. Vascular and muscular involvement is usually absent, probably explaining the lack of functional impairment and symptomatic presentation.

PRIMARY AMYLOIDOSIS OF THE TESTIS AND PARATESTICULAR TISSUE

Testicular involvement by amyloidosis is extremely rare, and all reported cases were results of secondary involvement by systemic amyloidosis.^42,49,50 No primary localized amyloidosis of the testicular adnexa has been reported to date.

SUMMARY

Amyloidosis of the genitourinary tract is a rare disease that may mimic a neoplastic process both clinically and radiologically. A higher level of awareness of this entity is required by pathologists and clinicians for accurate diagnosis and patient.

management.

References

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