Introduction
Amyloidosis is a rare and complex systemic disorder characterized by the extracellular deposition of amyloid fibrils, which leads to progressive organ dysfunction. The most frequently affected organs are the heart, kidneys, and liver. Isolated involvement of other structures such as in genitourinary tract is uncommon. AL amyloidosis, or immunoglobulin light chain amyloidosis, arises from the misfolding and deposition of monoclonal immunoglobulin light chains, typically originating from plasma cell dyscrasias such as multiple myeloma (MM) and monoclonal gammopathy of undetermined significance. Isolated and localized AL amyloidosis without monoclonal gammopathy is exceedingly rare. The clinical presentation of systemic AL amyloidosis is insidious and often involves nonspecific symptoms that can mimic a wide range of systemic disorders. Common manifestations include cardiac involvement, which may lead to restrictive cardiomyopathy, arrhythmias, or congestive heart failure; renal impairment, presenting as nephrotic syndrome or proteinuria; and neuropathy, which may cause disabling peripheral or autonomic dysfunction [ 1 ]. Localized AL amyloidosis, however, presents with symptoms specific to the function or structure being affected and without any hallmark of monoclonal gammopathy or systemic dysfunction. The diagnostic approach to AL amyloidosis is multifaceted, involving both laboratory and histopathological assessments. Initial evaluation typically includes tissue biopsy establishing amyloid deposition with Congo red staining and a subtyping study such as liquid chromatography-mass spectrometry for the definitive identification of amyloid deposits. This is followed by serum and urine electrophoresis/immunofixation and free light chains assay to detect monoclonal proteins along with bone marrow and/or fat pad biopsy to evaluate for plasma cell dyscrasia [ 2 ].
In our case, AL amyloidosis was identified as the underlying etiology of urethral pathology. We describe a rare instance of isolated urethral AL amyloidosis in a 23-year-old male patient, who presented with urethral stricture and hematuria. We discuss the diagnostic approach, management, and the importance of follow-up in localized amyloidosis. By sharing this, we aim to enhance awareness of clinical manifestation of this condition and underscore the need for a thorough systemic evaluation in patients with atypical presentations.
Case Presentation
A 23-year-old male with no significant past medical history presented with a year long history of urethral bleeding and dysuria. The patient was found to have scar tissue around the penile urethra at the time of presentation. A retrograde urethrogram revealed a 3.5 cm stricture in the penile urethra, while the bulbar and prostatic urethra appeared unremarkable. Cystoscopy showed no bladder abnormalities. The patient underwent stage 1 urethroplasty, during which urethral stricture biopsy was obtained. Histopathological examination demonstrated Congo red staining amyloid deposition in the urethral connective tissue around blood vessels along with lambda-restricted plasma cells and polarized light microscopy demonstrated characteristic apple-green birefringence of the amyloid deposits ( Fig. 1 ). Electron microscopy of the tissue confirmed amyloid deposits in the blood vessel walls ( Fig. 2 ). Liquid chromatography tandem mass spectrometry on peptides extracted from Congo red-positive micro-dissected areas of the paraffin-embedded urethral tissue confirmed AL (lambda)-type amyloidosis.
A comprehensive workup was initiated to evaluate the potential for systemic AL amyloid involvement and to assess the degree of an underlying plasma cell disorder. Laboratory work showed normal renal and hepatic function. Minimal proteinuria (196 mg in 24 h) was noted. Cardiac biomarkers (troponins I and NT pro-BNP) were normal. Electrocardiography and echocardiography were negative for cardiac involvement.
To assess the extent of the plasma cell neoplasm, further diagnostic tests, including serum and urine protein electrophoresis and immunofixation (SPEP, SIFE), serum free light chain assay, bone marrow biopsy and aspirate, and fat pad biopsy, were performed ( Fig. 3 ). All tests failed to demonstrate any evidence of systemic involvement of AL – amyloidosis or plasma cell neoplasm. The amyloid deposits were exclusively confined to the urethra. Subsequently, the patient underwent stage 2 urethroplasty to optimize urethral flow and ensure long-term functional restoration. The patient is free of local/systemic recurrence of amyloidosis and monoclonal gammopathy a year out of diagnosis and has reported no urinary complaints. Efforts to obtain the patient’s perspective were limited by inconsistent follow-up and barriers to sustained communication.
Discussion
Urethral amyloidosis, a rare manifestation of systemic amyloidosis, is characterized by the deposition of amyloid fibrils within the urethral wall, leading to progressive narrowing, fibrosis, and associated obstructive symptoms. While amyloidosis is more commonly observed in organs such as the heart, kidneys, and liver, isolated organ or site involvement is very uncommon. Isolated involvement of genitourinary tract, especially urethra, remains exceedingly rare. AL amyloidosis is typically associated with the overproduction of monoclonal immunoglobulin light chains by clonal plasma cells in association with monoclonal gammopathy but with lower volume disease [ 2 ]. These light chains aggregate into insoluble amyloid fibrils, which deposit in various tissues, causing organ dysfunction.
In urethral amyloidosis, infiltration of amyloid fibrils into the submucosal layers of the urethra leads to progressive fibrosis, which in turn results in luminal narrowing and urinary obstruction. The clinical presentation of urethral amyloidosis commonly involves obstructive uropathy due to urethral strictures and hematuria as in our case. While AL amyloidosis typically manifests with systemic involvement, this case presented here underscores the potential for amyloid deposits to be confined exclusively to a single site. This localized presentation highlights the heterogeneous nature of amyloidosis and presents a diagnostic challenge and the importance of differentiating it from other causes of urethral obstruction, such as carcinoma. The diagnosis of urethral amyloidosis is primarily confirmed through biopsy, which in our case demonstrated the presence of amyloid deposits and presence of lambda-restricted plasma cells. A case series by Fujihara and Glenner [ 3 ] of 11 cases of primary localized amyloidosis of the genitourinary tract showed preponderance of AL amyloidosis (82% or 9/11 cases demonstrating lambda light chains on biopsy via immunostaining) [ 4 ]. Excluding this case series, we found mention of over 50 cases of urethral amyloidosis in our review of literature in PubMed. Of those cases, we highlight 3 cases of localized urethral AL amyloidosis with sufficient data to report [ 5 – 7 ] ( Table 1 ). A brief summary of these 3 cases and comparison of key findings to our case ( Table 1 ) is presented below.
Table 1.
Comparison of cases of isolated urethral AL amyloidosis in literature
AL, amyloidosis; AA, secondary.
| Feature | This Case | Noone and Clark [ 7 ] | Asl et al. [ 5 ] | Mangera et al. [ 6 ] |
| Age | 23 years | 28 years | 29 years | 42 years |
| Presentation | One year of dysuria and hematuria | Two years of dysuria, hematuria, and tender periurethral mass erection | Dribbling of urine after micturition and occasional blood in underwear for unreported duration | Two years of dysuria and painful erection |
| Imaging findings | Retrograde urethrogram and cystoscopy: stricture in penile urethra | Retrograde urethrogram and cystoscopy: irregular narrowing of penile urethra, extensive bladder trabeculation; soft tissue X-ray of penis demonstrating periurethral calcifications | Not reported | Not reported |
| Urethroscopy | Mask-like scar tissue in penile urethra | White, friable plaques in penile urethra | Obstructive lesion of urethra and difficulty passing urethroscope | Not reported |
| Systemic workup | Negative for plasma cell dyscrasia, negative fat pad biopsy, negative for liver, heart, and kidney involvement | Not reported | Negative for plasma cell dyscrasia, normal renal function. Bone marrow biopsy not preformed | Negative for rheumatologic disorder, plasma cell dyscrasia, negative skeletal survey, and negative bone marrow biopsy |
| Diagnosis method | Urethral biopsy: submucosal amyloid deposition positive on Congo red staining; lambda-restricted plasma cells on in situ hybridization | Urethral biopsy positive for Congo red; special stains ruled out AA (secondary) subtype | Urethral biopsy positive for Congo red; immunostaining positive for polyclonal anti-λ light chain | Urethral biopsy: immunostaining confirmed AL amyloid |
| Liquid chromatography mass spectrometry showed AL type amyloid | ||||
| Amyloid type | AL, lambda | Presumed AL | AL, polyclonal lambda | AL, unknown light chain type |
| Treatment approach | Two-stage urethroplasty | Not reported | Surgical resection | Patient refused treatment |
In a report by Noone and Clark [ 7 ], primary isolated urethral amyloidosis was identified in a 28-year-old male presenting with periurethral mass and obstructive voiding symptoms. Retrograde urethrogram and cystoscopy evaluation revealed strictures along the penile urethra. Biopsy and Congo red staining confirmed localized amyloid deposition, with no evidence of systemic disease [ 7 ]. Asl et al. [ 5 ] reports a case of a 29-year-old male who presented with occasional blood in his underwear and dribbling after micturition. This patient was diagnosed with AL amyloid of the urethra with urethral biopsy and immunostaining [ 1 ]. However, the amyloid protein comprised polyclonal lambda light chains as opposed to monoclonal lambda light chains in our report. Mangera et al. [ 6 ] described a case of a 42-year-old male who presented with 2 years of dysuria and painful erection. Diagnostic confirmation was achieved by urethral biopsy, and AL amyloid of the urethra was confirmed through immunostaining [ 6 ]. These 3 cases illustrate the heterogeneous presentation of urethral amyloidosis and underscore the critical role of histopathological evaluation in guiding diagnosis and management.
Isolated amyloidosis should be considered in the differential diagnosis of urethral pathology, particularly in the absence of systemic features. The challenge in distinguishing urethral amyloidosis from urothelial carcinoma is particularly notable, as both conditions may present with similar clinical symptoms, including hematuria, stricture/periurethral nodule, and obstructive urinary symptoms. Furthermore, the radiological features of both conditions can overlap, necessitating a high index of suspicion and reliance on histopathological confirmation [ 8 ].
It is essential to accurately subtype amyloid, which may be done using different modalities including liquid chromatography tandem mass spectrometry. In cases of AL amyloidosis, a comprehensive systemic workup is essential to rule out potential systemic involvement. Our patient exhibited no evidence of systemic disease following an extensive evaluation. More commonly, AL amyloidosis is frequently associated with smoldering MM or symptomatic MM, with an estimated 10–15% of MM patients developing amyloidosis during their disease. The smoldering phase of MM, an intermediary stage between MGUS and full-blown MM, can predispose to amyloid deposition and thus warrants heightened surveillance [ 2 ]. This relationship underscores the critical need for a comprehensive and systematic approach to diagnosing and managing amyloidosis, particularly when presenting with rare and localized manifestations such as urethral amyloidosis.
The management of urethral amyloidosis predominantly involves surgical intervention. In cases where amyloid deposits result in urethral stricture, urethroplasty is the primary treatment modality. In our case, 2-staged urethroplasty was performed to optimize urethral flow and ensure long-term symptom resolution. Buccal mucosa grafting is commonly employed in stage 2 procedures as it provides an effective means to reconstruct long-segment strictures, offering favorable outcomes in terms of urinary function and stricture relief. Due to the non-keratinized, fibrous-resistant nature of buccal mucosa, it is beneficial in the treatment of complex urethral strictures [ 9 ]. To date, urethroplasty has been reported in a limited number of cases for the management of urethral amyloidosis. We found 2 cases where the authors reported employing buccal mucosa grafting with long-term follow-up. Mangera et al. [ 6 ] described 2 cases of urethroplasty to treat urethral amyloidosis with no evidence of recurrence at 2-year follow-up for both the penile skin flap and buccal mucosa graft techniques [ 6 ]. Similarly, Yao et al. [ 10 ] reported an additional 2 cases, similarly demonstrating no recurrence at 18 months and 6 months during follow-up for urethroplasty with buccal mucosal graft and penile flap, respectively [ 9 ]. These findings suggest that urethroplasty may offer durable disease control in select patients in comparison to urethral dilation.
The prognosis of AL amyloidosis is largely determined by the extent of organ involvement at the time of diagnosis, with cardiac and renal involvement being the most significant predictors of poor outcomes. Untreated patients with severe cardiac amyloidosis have a median survival of less than 1 year, whereas early intervention with therapies aimed at reducing amyloid production can lead to significant improvements in survival and quality of life [ 11 ]. Early recognition of apparent localized amyloidosis as a component of systemic disease is crucial as it facilitates timely treatment and may avert irreversible organ damage as a result of progression of unrecognized monoclonal disorder. Systemic amyloidosis, given its widespread organ involvement, often necessitates a more aggressive, multipronged therapeutic approach, which may include anti-CD38 monoclonal antibodies, proteasome inhibitors, chemotherapy, and autologous stem cell transplantation aimed at controlling the underlying plasma cell dyscrasia. Conversely, the localized form, as exemplified in the present case, calls for a more focused, surgical intervention, typically aimed at addressing the specific site of amyloid deposition – in this case, the urethra. This distinction, if made early in the diagnostic process, ensures the deployment of the most appropriate treatment [ 12 ].
This case highlights the critical role of comprehensive diagnostic workup in confirming the localized nature of amyloidosis as well as formulating proper follow-up plan. This ensures that the management approach is not only precise but also tailored to the patient’s specific clinical needs, thereby optimizing outcomes while minimizing unnecessary interventions. In localized AL amyloidosis, the risk of future monoclonal disorder is difficult to determine due to its rarity as only a handful of cases have been reported in literature. As a result, it is important to adopt a precautionary approach with continued observation for systemic involvement at least yearly [ 6 ]. Evidence-based surveillance protocol is however lacking.
Conclusion
This case highlights the importance of considering isolated urethral amyloidosis in the differential diagnosis of urethral strictures presenting with obstructive urinary symptoms and hematuria. Despite its rarity, urethral amyloidosis should be suspected when conventional causes of stricture are excluded. Early recognition and biopsy confirmation are crucial as they allow for timely intervention, such as urethroplasty, to restore normal urinary function. Additionally, a thorough workup to evaluate amyloid subtype and exclude systemic amyloidosis should be undertaken. Localized AL amyloidosis is a diagnosis of exclusion made after negative evaluation for systemic involvement and confirming absence of plasma cell dyscrasia. Extended follow-up to detect resurgence of monoclonal disorder is necessary every 6 months, though there has been challenges in following up with the patient mentioned in this case.
Acknowledgment
We are grateful for Mayo Clinic Laboratory for performing liquid chromatography tandem mass spectrometry (LC-MS) on urethral specimen.
Statement of Ethics
Ethics approval is not required for this study in accordance with local and national guidelines. Written informed consent was obtained from the patient for publication of the details of his medical case and any accompanying images. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000547759 ).
Conflict of Interest Statement
The authors have no conflict of interest to declare.
Funding Sources
There was no funding in relation to this work.
Author Contributions
M.C. wrote the case report and performed the literature search. N.R.K. treated the patient. N.R.K., S.H., and O.A. reviewed and edited the manuscript. R.C. interpreted all of the pathology studies and wrote the legends.
Funding Statement
There was no funding in relation to this work.
Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study. Further inquiries can be directed to the corresponding author.
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Associated Data
Supplementary Materials
Data Availability Statement
Data sharing is not applicable to this article as no new data were created or analyzed in this study. Further inquiries can be directed to the corresponding author.