Spontaneous bilateral peri-orbital purpura: an important clinical sign of primary systemic amyloidosis

Abstract

A 69-year-old woman presented with an 18-month history of recurrent bruising of the eyelids. She was otherwise asymptomatic and systems review was unremarkable. On examination, she had peri-orbital purpura and waxy papules at the inner canthus of both eyes. Macroglossia was also noted. Subcutaneous abdominal biopsy identified amorphous material in the dermis that stained positive for Congo red, with apple-green birefringence seen under polarised microscopy. Immunohistochemistry demonstrated antibodies against lambda light chains. Bone marrow biopsy identified further deposits of immunoglobulin light chain amyloid and a clonal infiltrate with 10%–20% plasma cells, confirming amyloidosis secondary to multiple myeloma. Iodine-123-labelled serum amyloid protein scintigraphy showed no abnormal uptake, thereby excluding significant amyloid deposits in the liver, spleen or kidneys. Cardiac MRI was consistent with early amyloid infiltration. We highlight the importance of dermatological manifestations in amyloidosis, to allow for early diagnosis, potentially limiting end organ involvement.

Background

The skin is an important marker of underlying systemic pathophysiology. This is of particular significance in amyloidosis, a multi-systemic condition where dermatological signs may be the only evidence of disease at diagnosis in as many as 40% of cases.¹ This case report details the diagnosis of amyloidosis in one such patient. Although our patient had very few symptoms to suggest systemic disease, a number of organ systems had been infiltrated by amyloid at the time of diagnosis. Given that presenting symptoms in amyloidosis can be vague and varied, delayed diagnosis is common. This delay can result in significant morbidity and mortality for the patient. Prompt identification of dermatological signs can provide the opportunity for earlier diagnosis and specialist intervention, potentially limiting or delaying end organ damage.

Case presentation

We present the case of a 69-year-old woman who was referred to dermatology with an 18-month history of recurrent bruising around her eyelids. There was no history of trauma or precipitating factors. She had a medical history of hypertension, for which she took perindopril, and rheumatoid arthritis, though she was not on any regular medication for this. She was not taking any antiplatelet or anticoagulant medication. She was otherwise healthy, with no systemic symptoms, and review of systems was non-contributory. She was a non-smoker and did not drink alcohol.

On examination, she had non-tender, purpuric papules in the periorbital area, primarily affecting the superior palpebral folds (figure 1). Dome- shaped waxy nodules were also evident at the inner canthus of the eyes (figure 2). On general inspection, macroglossia was noted to be present, with indentation and scalloping from her dentition seen at the lateral margin of the tongue (figure 3).

Figure 1.

Non-tender peri-orbital purpuric papules.

Figure 2.

Waxy, dome-shaped nodules at the inner canthus of the eyes.

Figure 3.

Macroglossia.

Differential diagnosis

The differential diagnosis for this presentation includes primary cutaneous nodular amyloidosis, where amyloid deposits are limited to the skin, with no systemic involvement. It remains important in primary cutaneous nodular amyloidosis to investigate for systemic amyloidosis, given the overlap in clinical presentation.²

Other differentials included papular mucinosis, characterised by mucin deposits in the skin and lipoid proteinosis, a rare genetic disorder due to a loss of function mutation in a gene encoding extracellular matrix protein 1. Systemic differential diagnoses were also considered, including granulomatous disorders such as sarcoidosis. However, the peri-orbital distribution of cutaneous findings in this case led to our working diagnosis of amyloidosis. Ultimately, skin biopsy was required to establish a histopathological diagnosis, thereby guiding further investigation.²

Investigations

Baseline investigations revealed a normal full blood count, liver profile and renal function. Urine protein–creatinine ratio was elevated at 142 (ULN <15), though nephrotic range proteinuria was not identified. Serum protein electrophoresis was normal and did not identify a paraprotein; however, serum lambda free light chains were elevated at 767.9 mg/L (reference range: 5.7–26.3 mg/L) and serum-free kappa/lambda ratio was 0.05 (normal range: 0.26–1.65). Beta-2 microglobulin, which can be raised in haematological malignancy, was 5.1 mg/L (reference range: 1.2–2.5 mg/L).

Subcutaneous abdominal biopsy identified a focus of amorphous, hyaline material in the upper dermis that stained positive for Congo red (figures 4 and 5), with apple-green birefringence seen under polarised microscopy (figure 6). Immunohistochemical staining was performed, using specific antibodies that react with serum amyloid A protein and with kappa and lambda immunoglobulin light chains. This specimen stained positively for lambda light chains, confirming the presence of amyloid in the skin. We did not biopsy the affected skin, given its peri-orbital distribution. In diagnosing amyloidosis, biopsy of a surrogate site such as the abdominal fat pad can provide evidence of diagnosis, as asymptomatic infiltration of the subcutaneous fat and dermal vessels is common. Subsequent bone marrow biopsy identified further amyloid deposits in the bone marrow, with immunohistochemical staining confirming immunoglobulin light chain (AL) amyloidosis. There was also evidence of a clonal plasma cell infiltrate with 10%–20% plasma cells, confirming multiple myeloma.

Figure 4.

Skin biopsy with amorphous eosinophilic material in dermal blood vessels.

Figure 5.

Congo red staining showing amyloid deposits staining salmon in colour.

Figure 6.

Apple-green birefringence seen on polarised microscopy, consistent with amyloid.

On the basis of the clinical presentation, supported by the haematological and histopathological findings, a diagnosis of AL amyloidosis secondary to multiple myeloma was confirmed. Further investigations focused on identifying further amyloid deposits and establishing any evidence of end organ damage. A skeletal survey was performed, which did not identify any lytic lesions. Renal ultrasound showed sonographically normal kidneys. ECG was normal, though N- terminal- Pro-Brain Natriuretic Peptide (NT-proBNP) was elevated at 814 pg/mL. Echocardiogram demonstrated an ejection fraction of 55% with no visible amyloid deposits. Our patient was referred for further assessment in the National Amyloidosis Centre in the Royal Free Hospital in London. Iodine-123-labelled serum amyloid protein (SAP) scintigraphy was performed and showed no significant amyloid deposition in the liver, spleen or kidneys. Cardiac MRI suggested early amyloid infiltration with Mayo stage 2 disease biomarkers.³

Treatment, outcome and follow-up

Treatment of amyloidosis follows a tailored approach based on both patient factors, including age and general health, and disease factors of amyloid burden and organ involvement. The aim of treatment is to slow progression of amyloidosis by reducing amyloid forming precursor proteins, thereby delaying amyloid deposition, reducing symptom severity and maintaining quality of life for patients. On confirmation of cardiac amyloid, our patient was commenced on treatment with cyclophosphamide, bortezomib and dexamethasone. Response to treatment is measured with serial free light chain concentration. Given the multi-systemic nature of amyloidosis, our patient will also be followed up by nephrology to monitor any evidence of renal dysfunction.

Discussion

Primary systemic amyloidosis is a group of disorders caused by deposition of misfolded amyloid fibrils in extracellular tissues, resulting in progressive organ dysfunction.⁴ AL amyloidosis, the most common subtype of amyloidosis, is typically driven by an underlying plasma cell disorder, including multiple myeloma, Waldenstrom macroglobulinaemia, or lymphoproliferative disorder, such as non-Hodgkin’s lymphoma.⁴ Five hundred to six hundred new cases of amyloidosis are diagnosed each year in the UK.⁵ Given the multi-systemic nature of amyloidosis, presenting symptoms can be varied and can mimic more common conditions, often leading to delayed diagnosis. Dermatological manifestations are seen in up to 40% of patients with AL amyloidosis, thereby providing an opportunity for early diagnosis.¹

A number of case reports have described cutaneous manifestations of systemic amyloidosis.^6–8 In these cases, patients presented with extensive nodular, indurated, bullous lesions or cutis laxa. Our case highlights that more subtle cutaneous signs can herald advanced systemic disease in amyloidosis. Typical sites for cutaneous involvement include orbits, nares, mouth and genitala, due to fragility of blood vessels at these sites.² Cutaneous involvement most commonly has a purpuric appearance due to the deposition of amyloid in superficial blood vessels.² However, contrary to popular teaching, peri-orbital papules do not always present with pupura. It is important to have a high index of suspicion for further investigation for amyloidosis in all patients presenting with unexplained peri-orbital infiltrative dermatoses.⁹

The diagnosis of amyloidosis is based on the histologic identification of amyloid fibrils in an affected organ. However, given the systemic nature of amyloidosis, biopsy of a surrogate site, such as an abdominal fat pad, can provide evidence for diagnosis. Classical histologic features of amyloidosis include the presence of pink amorphous material that stains with Congo red dye. When examined under polarised microscopy, the deposits display apple- green appearance.⁴ Typing of amyloid has relied on immunohistochemical staining with antibodies to kappa and lambda light chains, or more advanced techniques such as proteomics.¹⁰

Further investigations are required to assess the extent of amyloid deposition and look for an underlying plasma cell dyscrasia. Baseline blood tests, including full blood count, coagulation profile, renal profile and liver function tests, are performed to identify any evidence of organ failure or infiltration. Bone marrow biopsy, serum and urine protein electrophoresis and free light chain assessments are performed to outrule the presence of a clonal plasma cell line.⁴

Skeletal survey is undertaken to identify any lytic lesions in the investigation of multiple myeloma. Urine protein–creatinine ratio and 24-hour collection for protein quantification are the initial investigations for renal involvement. NT-proBNP, ECG and echo are done to establish if there is any evidence of cardiac involvement. Cardiac deposits of amyloid are present in approximately 60% of patients and can progress to restrictive cardiomyopathy.¹¹ Increases in NT-proBNP typically precede the onset of clinical heart failure symptoms and are important predictors of outcome in amyloidosis. Amyloid-specific imaging, such as SAP scintigraphy and cardiac MRI, where available, are the gold standard for non-invasive assessment of the extent of amyloid deposition.¹¹

The goal of treatment in AL amyloidosis is to reduce production of the amyloid precursor proteins, thereby limiting further amyloid deposition and delaying progression to end organ failure. This is done by targeting the plasma cells forming the abnormal immunoglobulins. The choice of treatment in amyloidosis is determined by several factors, including disease burden, degree of end organ damage and patient comorbidities. Treatment of amyloidosis can be associated with significant mortality and appropriate patient selection is important to mitigate this. Combination chemotherapy regimes similar to those used in myeloma have positive outcomes. Bortezomib–alkylator–steroid combination regimes are preferred where rapid response to treatment is required, as is the case in cardiac amyloidosis.

Learning points.

• Amyloidosis can present with a variety of dermatological signs, where skin manifestations are the only evidence of disease at diagnosis. The lesions usually reflect capillary infiltration and fragility with petechiae and purpura. A variety of subtypes of amyloid can affect the skin.

• Systemic immunoglobulin light chain (AL) amyloidosis is the most common type and purpura or waxy nodular lesions in the peri-orbital area are frequent.

• Localised cutaneous AL amyloidosis can manifest as capillary fragility, xanthomatous papules, hyperpigmented keratotic lesions, scleroderma-like changes and bullous lesions.

• As this case report highlights, clinicians require a high index of suspicion in diagnosing the sometimes subtle dermatological signs associated with amyloidosis. Prompt identification of such signs provides the opportunity for earlier diagnosis and treatment, potentially limiting further amyloid infiltration and end organ damage.