False negative biceps tendon sampling for detection of systemic amyloidosis: a case report

Amyloidosis is a group of disorders which have in common a pathologic process characterized by the extracellular deposition of insoluble protein aggregates in peripheral tissues and organs.^9,14 There are many types of amyloidosis, and the most common types include amyloid light-chain fragment, amyloid A protein, and transthyretin amyloidosis (ATTR).^1,2 In addition, ATTR may occur as a wild-type transthyretin amyloidosis (wtATTR) protein that is associated with aging or as hereditary transthyretin amyloidosis mutation associated with familial inheritance.^1,2 The incidence of amyloidosis is reported at 9.7-14 cases per million people annually.^1,2 Although, many believe amyloidosis is underdiagnosed secondary to nonspecific clinical presentations and overlapping medical conditions. Depending on the type of amyloidosis, amyloid accumulation throughout the body can have many clinical manifestations including cardiomyopathy, hepatomegaly, neuropathy, renal failure, hypertension, and ophthalmic dysfunction.⁹ The polyneuropathy and musculoskeletal manifestations of systemic amyloidosis include carpal tunnel syndrome, lumbar stenosis, osteoarthritis of the hip, knee and shoulder, rotator cuff tear, biceps rupture, and trigger digits.^10,12,15

Historically, initial diagnosis of ATTR was in the setting of advanced cardiomyopathy where treatment options were limited and poor outcomes were expected. Advanced ATTR amyloidosis has a poor prognosis without treatment, but effective disease-modifying treatments are available when the disease is caught in the earlier stages.^4,11 The polyneuropathy and musculoskeletal manifestations of systemic amyloidosis can have early clinical manifestations that present years prior to the onset of the cardiac manifestations.⁷ In the setting of suspected ATTR, a tiered algorithm for tissue biopsy can be utilized when performing an open carpal tunnel release (CTR) technique to provide an early identification of systemic amyloidosis.^5,6 In addition, many studies have reported the presence of amyloid deposition detected at common orthopedic surgeries other than carpal tunnel syndrome (transverse carpal ligament and flexor tenosynovium), including hip and knee osteoarthritis (synovium and articular cartilage), lumbar spinal stenosis (ligamentum flavum), and rotator cuff tears (tendon).¹⁵ Thus, tissue biopsy in the setting of common orthopedic surgeries has growing evidence as an effective tool for early identification of amyloidosis.

While reports of biceps tendon rupture has been shown to be associated with amyloidosis, to our knowledge, there has not been an investigation evaluating biceps tendon tissues taken in routine orthopedic shoulder surgeries as a potential site for amyloidosis biopsy.¹⁰ The purpose of this case report is to highlight the need for caution when ruling out amyloidosis after performing diagnostic biopsies in routine orthopedic surgeries.

Case presentation

A 58-year-old male with a 40-year history of recurrent lumbar herniated discs presented with progressive neurogenic claudication refractory to conservative management. He subsequently underwent revision decompression surgery (L2-L4) in January 2020.

Three months later, he presented for evaluation of bilateral carpal tunnel syndrome and trigger fingers and underwent surgical release of the right index and ring trigger fingers in June 2020. Over the following 2 years, he was treated with nonoperative management for his bilateral carpal tunnel syndrome and persistent left hand trigger fingers. He eventually underwent surgical release of the left index and middle trigger fingers in April 2022.

In July 2023, he was found to have a full-thickness subscapularis tendon tear and long head biceps subluxation. An arthroscopic rotator cuff repair (RCR) and biceps tenodesis were performed in August 2023. Due to growing concern for systemic amyloidosis in this patient and the association of biceps pathology in systemic amyloidosis, a tenosynovial biopsy of the biceps tendon was performed at the time of the biceps tenodesis, which was negative for amyloid deposition with Congo red staining at this time.

Most recently, in February 2024, he underwent left carpal and cubital tunnel release. A routine tenosynovial biopsy revealed amyloid deposition on Congo red stain, subsequently confirmed as wtATTR amyloidosis by liquid chromatography tandem mass spectrometry. Evaluation for cardiac amyloidosis revealed no involvement with Technetium-99m pyrophosphate scintigraphy. Genetic testing via Invitae hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) test was negative for hereditary transthyretin (TTR). He subsequently was started on Tafamidis and is routinely following up with his cardiologist. Tafamidis is a TTR kinetic stabilizer that binds to the TTR protein and inhibits amyloid formation.³ He has not developed any new cardiac manifestations at his latest follow-up. In addition, he has undergone right carpal and cubital tunnel release without complications.

Discussion

Transthyretin amyloidosis can present with various musculoskeletal pathologies. Prompt diagnosis and treatment with new therapies can delay life-threatening manifestations and increase survival.^4,11 Early musculoskeletal manifestations of amyloidosis can present as carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, osteoarthritis as well as other reported arthropathies and neuropathies.^10,12,15 In practice, orthopedic surgeons should have high suspicion for systemic amyloidosis in patients greater than 50-year-old that present with multiple musculoskeletal findings. Review of the patient's medical history may show chronic musculoskeletal pain or numerous nonoperative therapies to remedy these manifestations. Left undiagnosed, ATTR can eventually lead to widespread end-organ disease. Orthopedic surgeons can not only treat their patient's orthopedic issues but can potentially aid in diagnostic confirmation of amyloidosis in their practice.

Due to the substantial value of early diagnosis, some surgeons routinely collect tissue biopsies in surgery when amyloidosis is suspected.^13,15 The authors believe that the addition of these biopsies into clinical practice adds little burden in the operating room, as the tissues are easily accessible during surgery. Although we also acknowledge that the diagnostic value of tissue biopsy in many sites is not well studied in the literature. It has been reported that up to 30% of patients with positive biopsies during CTR need further medical treatment.^8,13 Early diagnosis allows expedited care and improves long-term outcomes for patients with amyloidosis.^4,11 Biceps tendon rupture has been associated with systemic amyloidosis and may warrant referral for additional evaluation. However, the diagnostic efficacy of the biceps tendon biopsy in the evaluation of amyloidosis is not known.¹⁰

This case involves a 58-year old male with a history of RCR and CTR with tissue biopsies for evaluation of amyloidosis. The biceps tendon biopsy during the RCR was negative on Congo red staining, while the tenosynovial biopsy during CTR was positive less than a year later. The patient subsequently was referred for appropriate additional work up and treatment with cardiology. This case report supports the use of the carpal flexor tenosynovium as a site for earlier detection of amyloidosis. In addition, this case highlights the low threshold for repeat biopsy when clinical suspicion for amyloidosis is high. While biceps tendon rupture has been shown to be associated with amyloidosis, there is still no strong evidence regarding the efficacy of biceps tendon biopsy during shoulder surgery for detection of amyloidosis.

Conclusion

This case report documents detection of wtATTR after carpal flexor tenosynovium biopsy in a 58-year-old male 1 year after a negative biceps tendon biopsy during RCR. Detection of these amyloid deposits prior to the onset of cardiovascular symptoms allows for earlier diagnosis of systemic amyloidosis, which allows clinicians to utilize more treatments to manage symptoms, slow disease progression, and increase survival. When surgically managing patients with musculoskeletal pathologies associated with systemic amyloidosis, physicians need to maintain a high clinical suspicion for this disease regardless of prior negative biopsy results.

Disclaimers:

Funding: No funding was disclosed by the authors.

Conflicts of interest: The authors, their immediate families, and any research foundation with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.

Patient consent: Obtained.