Wild-type ATTR amyloidosis of the prostate: a case review

Abstract

The amyloidoses are a rare group of disorders caused by the deposition of amyloid fibrils in organ tissues. Transthyretin-mediated amyloidosis is a subcategory of amyloidosis, which can be further subdivided into hereditary transthyretin-mediated or wild-type (‘senile’) amyloidosis. Involvement of the prostate by any type of amyloidosis is rare, with only a handful of cases reported in the literature. We report here a case of a 64-year-old Caucasian man who was incidentally found to have wild-type transthyretin-mediated amyloidosis of the prostate following a radical prostatectomy for treatment of a localised, Gleason 7 (4 + 3) adenocarcinoma of the prostate. TTR subtyping was confirmed by mass spectrometry. His family history was negative for known amyloidosis, and sequencing of the entire TTR gene was negative for any mutations, so he was therefore considered to have wild-type TTR amyloidosis. He was subsequently found to have additional foci of amyloid deposition in the gastrointestinal tract. Wild-type transthyretin-mediated amyloidosis as an incidental finding in a prostate biopsy is an extremely rare finding. Treatment options for transthyretin-mediated amyloidosis are limited, and further research and treatment options are needed in this rare and difficult to manage disease.

Level of evidence: The level of evidence according to the Oxford Centre of Evidence-based Medicine levels of evidence is not applicable to this case report. Given that this is a rare entity, decisions made in managing this case were based on a level of evidence of 5.

Introduction

The amyloidoses are a group of disorders caused by the deposition of insoluble amyloid fibrils in organ tissues. ¹ The major subcategories of amyloidosis include: primary or light chain (AL), associated with plasma cell dyscrasias; secondary (AA), associated with chronic inflammatory states and transthyretin-mediated (ATTR). ATTR amyloidosis can be further subdivided into hereditary ATTR, caused by mutations in the TTR gene, or wild-type (‘senile’) ATTR, which has a poorly understood pathophysiology and is most commonly seen in the elderly population.

The amyloidoses are rare, with a collective incidence of approximately 0.5–1 cases per 100,000 person-years, and a peak incidence at 60–79 years.^2,3 Frequently involved organs include the heart, kidneys, peripheral nervous system and gastrointestinal tract. ⁴ Involvement of the genitourinary tract is uncommon, although amyloidosis of the seminal vesicles and the bladder are both recognised entities, and amyloidosis of the bladder in particular is clinically important for urologists as it can mimic bladder cancer. ⁵ Amyloidosis of the prostate is exceptionally rare, with only a handful of cases reported in the literature.^6–8

We report here a case of wild-type ATTR amyloidosis of the prostate discovered incidentally following radical prostatectomy.

Case review

A 64-year-old Caucasian man was referred to urology by his family physician for a rising prostate specific antigen (PSA). Past medical history was significant for coronary artery disease, hypertension, dyslipidemia, lumbar spinal stenosis, osteoarthritis and remotely diagnosed carpal tunnel syndrome with three prior release surgeries. He underwent a transrectal biopsy of his prostate, consisting of 12 cores at 10 sites, which revealed prostatic adenocarcinoma in 3/10 sites (4/12 cores) with a Gleason score of 7 (4+3) at all sites. The preoperative PSA was 7.0 µg/L. A preoperative computed tomography (CT) scan showed the prostate measuring 60 cc with no periprostatic fat stranding or lymph nodes. A preoperative magnetic resonance imaging (MRI) was not performed. He underwent robot-assisted laparoscopic radical prostatectomy and bilateral pelvic lymph node dissection. Pathology from the specimen revealed pT3a, pN0, Gleason 7/10 (4+3) prostatic adenocarcinoma, with extraprostatic extension and lymphovascular invasion and negative for seminal vesicle involvement. Following his operation, he was found to have a rising PSA, and he subsequently underwent salvage radiotherapy. He is currently well 4 years postoperatively and his most recent PSA is 0.1 µg/L.

Incidentally, he was found to have amyloid deposition within some of the arterial walls in the prostate and the periprostatic tissue. Immunohistochemistry was positive for TTR, and negative for both kappa and lambda light chains. TTR subtyping was confirmed by mass spectrometry.

Serum haematology and chemistry panels were unremarkable. His serum free light chain assay, serum and urine protein electrophoresis and immunofixation were negative for a monoclonal protein. His troponin I and brain natriuretic peptide were normal, and an echocardiogram was unremarkable. Nerve conduction studies confirmed the presence of bilateral carpal tunnel syndrome.

His family history is negative for known amyloidosis, and there is no family history suggestive of a recurring amyloid syndrome. Sequencing of the entire TTR gene was negative for any mutations. Therefore, he is considered to have wild-type TTR amyloidosis.

Two years after his initial diagnosis, he developed abdominal pain and diarrhoea. He underwent lower and upper endoscopy, revealing amyloid deposition in the rectum, colon, duodenum and stomach. He was started on cholestyramine and his diarrhoea improved significantly. He is currently doing well and continues to be followed by haematology.

Discussion

Amyloidosis can present either systemically or locally, and patients with amyloidosis affecting one organ system are often found to have amyloid deposition in other organs even in the absence of symptoms.^9,10 In our patient’s case, he did not appear to have any symptoms related to prostatic amyloid. However, the presence of prostatic amyloid prompted his clinicians to consider amyloidosis of the gastrointestinal tract as a cause of his symptoms of abdominal pain and diarrhoea, which ultimately proved to be correct. Incidental findings of amyloid on a pathology specimen should prompt consideration of a thorough work-up for systemic amyloidosis, particularly if a patient has clinical symptoms that are otherwise unexplained. A recent review describing six patients with incidentally discovered prostatic ATTR amyloidosis indicated that five of the six patients also had or subsequently developed cardiac amyloidosis, suggesting that a thorough cardiac work-up is particularly important to perform in these patients. ⁸

In AL and AA amyloidosis, treatment is usually aimed at addressing the underlying plasma cell dyscrasia (AL) or the underlying inflammatory disorder (AA). Unfortunately, treatment options for wild-type ATTR amyloidosis are limited and the prognosis is poor. Patients typically experience progressively debilitating symptoms related to cardiac dysfunction and peripheral neuropathy, ¹¹ and have a median survival from diagnosis of 56.8 months. ¹² Fortunately, tafamidis, a small-molecule transthyretin stabiliser, has been shown to reduce all-cause mortality, decrease hospitalisation rates, and improve functional outcomes in patients with cardiomyopathy caused by either hereditary or wild-type ATTR amyloidosis. ¹³ Two additional agents have also recently been approved by the US Food and Drug Administration for the treatment of the hereditary form of ATTR amyloidosis,^14,15 although it is unclear if these agents will also demonstrate efficacy in wild-type ATTR.

Wild-type ATTR amyloidosis is a rarely reported incidental finding in a prostate biopsy. Gastrointestinal involvement of this type of amyloidosis has been reported, ¹⁶ but is also rare. ¹¹ In this patient, knowledge of the presence of ATTR amyloidosis in the prostate facilitated the subsequent diagnosis of gastrointestinal amyloidosis, underscoring the importance of a thorough review of systems and consideration of a complete diagnostic work-up in patients with an incidental finding of prostatic amyloidosis. Further research and treatment options are needed in this rare and difficult to manage disease.