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Cardiac AL amyloidosis presenting as recurrent dyspnoea in a patient with cancer: an important clinical clue to an early diagnosis
  1. Giselle Alexandra Suero-Abreu1,2,
  2. Phillip Lim1,
  3. Brijesh Patel3 and
  4. Renjit Thomas3
  1. 1Medicine, Rutgers University New Jersey Medical School, Newark, New Jersey, USA
  2. 2Cardiovascular Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  3. 3Cardiovascular Medicine, Rutgers University New Jersey Medical School, Newark, New Jersey, USA
  1. Correspondence to Dr Giselle Alexandra Suero-Abreu; giselle.suero{at}


Cardiac amyloidosis (CA) is challenging to diagnose due to its non-specific clinical manifestations early in the disease process. We report the case of a patient who presented with dyspnoea, abdominal distension and leg swelling. Medical history was notable for hypertension, recurrent vulvar squamous cell carcinoma and polysubstance abuse. Over 1 year before the official diagnosis of CA, the patient had multiple hospital readmissions for dyspnoea. Our case illustrates the importance of having a high index of clinical suspicion for an early diagnosis of CA. Furthermore, it highlights the need to re-evaluate a presumed diagnosis when a patient’s symptoms recur or do not respond to appropriate treatment and to consider the influence of social factors on diagnostic processes.

  • Heart failure
  • General practice / family medicine
  • Cancer - see Oncology
  • Gynecological cancer
  • cardio-oncology
  • cardiac amyloidosis

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Amyloid light chain (AL) amyloidosis is an uncommon yet underdiagnosed disease with an overall incidence of approximately 2500–5000 new cases per year in the USA.1 Although AL amyloidosis is a systemic disease affecting many organs, its cardiac involvement has been reported to determine patient outcomes significantly.2 3 CA has been shown to have the most severe pathogenesis and the worst prognosis compared with any other organs affected by AL amyloidosis.4 Despite a median survival after diagnosis of as short as 6 months, CA has been reported to be diagnosed over 1 year after initial presentation.5–9 Furthermore, approximately 33% of patients visit five or more physicians before being diagnosed.9 Given the advances in cardiac imaging and other diagnostic modalities, timely diagnosis is theoretically more feasible. However, reports suggest that isolated imaging findings may not be sufficient in an early CA diagnosis without a high index of clinical suspicion.10 These challenges in the setting of non-specific symptoms such as dyspnoea, lower extremity oedema, ascites and syncope make the diagnosis of CA early in the course of the disease difficult. CA is a disease that was once thought of as rare, but its true prevalence is becoming more apparent due to increased awareness, advances in diagnostics and increased life expectancies. We report the development of CA in a patient with multiple myeloma (MM) in the setting of recurrent vulvar squamous cell carcinoma (SCC) and high-grade human papillomavirus (HPV).

Case presentation

A female patient in her 50s with a medical history notable for SCC presented with exertional dyspnoea, worsening abdominal distension and leg swelling for 4 days. The patient reported walking approximately 1.5 meters before experiencing shortness of breath, orthopnoea and paroxysmal nocturnal dyspnoea. She also reported a non-productive cough, but denied wheezing, fevers, malaise or night sweats. Over the preceding several months, she experienced progressive weight loss but denied nausea, vomiting or diarrhoea. The patient denied chest pain or palpitations. On presentation, the patient had a temperature of 36.4°C, blood pressure of 123/98 mm Hg, heart rate of 104 beats per minute, respiratory rate of 18 breaths per minute and oxygen saturation of 96% on room air. The patient’s body mass index was 30.23 kg/m2. On physical examination, she appeared in mild respiratory distress and her right atrial pressure was estimated to be 10 cm H2O, with a positive hepatojugular reflux. Her cardiopulmonary examination was significant for diminished breath sounds and bibasilar crackles. The patient’s abdomen was distended, with a positive fluid wave and hepatomegaly appreciated on palpation. She had 2+ pitting lower extremity oedema up to her thighs bilaterally. Her medical history was significant for stage 4B vulvar SCC with metastasis to her right inguinal node, and she had bilateral inguinal femoral lymphadenectomy and radiation therapy 10 years prior to presentation. At that time, she had poor adherence to follow-up appointments in the setting of her opioid use disorder and she was deemed a poor candidate for chemotherapy. Six years after radiation therapy, the patient presented to the cardiology clinic with new-onset shortness of breath and an abnormal ECG suggestive of left atrial abnormality and prolonged QTc at 490 ms. At this time, the prolonged QTc was attributed to methadone use. A transthoracic echocardiogram (TTE) was scheduled, but the patient was lost to follow-up. Two years later, the patient was hospitalised for an acute ischaemic right middle cerebral artery stroke attributed to embolism of a newly discovered thrombus in the left atrial appendage on transoesophageal echocardiogram. At that time, the echocardiogram showed moderate concentric left ventricular (LV) hypertrophy (LVH) and grade 3 diastolic dysfunction (G3DD) but a normal LV systolic function. The patient was subsequently discharged on warfarin for anticoagulation.

Over the next year, the patient was hospitalised in several occasions for dyspnoea. Diagnoses at the time included acute decompensated heart failure with preserved ejection fraction (HFpEF) with G3DD, emphysema, pulmonary hypertension and pneumonia. Given a history of latent tuberculosis, the patient was also closely monitored with chest radiographs for a tuberculosis-related aetiology of her dyspnoea, which were negative. During her latest presentation, her ECG showed low QRS voltages and TTE showed preserved LV ejection fraction (LVEF) of 55% with a global longitudinal strain (GLS) of −13.4% with apical sparing. In terms of oncological history, at that time, the patient was found to have recurrence of SCC in the vagina, and a high-grade squamous intraepithelial lesion of the endocervix was diagnosed 1 year prior to presentation. Cytology was positive for HPV genotype 16 and other high-risk genotypes, but was negative for genotype 18.


Clinical studies were significant for chronic anaemia (haemoglobin 115 g/L), with renal and liver function tests within normal limits. Coagulation studies were normal, but the international normalised ratio (INR) was subtherapeutic at 1.3. HIV test was negative while urine drug screen was positive for methadone. On admission, a chest radiograph demonstrated cardiomegaly and a left-sided pleural effusion with no consolidations or pneumothorax (figure 1). ECG showed normal sinus rhythm, left axis deviation, diffuse low-voltage QRS complexes throughout the precordium and Q waves in the inferior leads suggestive of a pseudoinfarct appearance (figure 2A). An ECG from a year prior showed a more subtle possible pseudoinfarct pattern (figure 2B). CT scan of the chest, abdomen and pelvis showed a possible hypertrophic LV chamber with biatrial enlargement and bilateral pleural effusions (figure 3A). Additional CT findings included lytic lesions at the lumbar spine concerning for metastatic disease and hepatomegaly with hyperdense perihepatic lymphadenopathy and a large left adnexal cystic lesion (figure 3B). On review of her prior TTE studies, findings worsened over the year. It revealed a decreased LVEF of 43% from 65%, global hypokinesis, significantly thickened myocardium, G3DD, elevated pulmonary artery pressure of 46 mm Hg and a decreased GLS of −5.6% with apical sparing (‘cherry on top’) strain pattern concerning for CA (figure 4 and video 1). Doppler studies of the lower extremities were negative for acute or chronic deep vein thrombosis. Serum protein electrophoresis (SPEP) revealed monoclonal gammopathy with an elevated free kappa to lambda ratio. An abdominal wall fat pad excision biopsy showed Congo red-positive deposits with apple-green birefringence, confirming the diagnosis of AL amyloidosis (figure 5). A bone marrow biopsy revealed a new plasma cell dyscrasia consistent with MM.

Figure 1

Chest radiograph showing cardiomegaly and left-sided pleural effusion.

Figure 2

Resting ECG showing diffuse low QRS voltage and possible pseudoinfarct pattern as pathological Q waves in the inferior leads and in V3–V6 precordial leads at the time of latest admission (B) compared with an ECG a year prior (A) demonstrating only subtle changes.

Figure 3

CT scan of the chest, abdomen and pelvis showing a possible left ventricular hypertrophic chamber with left atrial and right atrial dilatation and bilateral pleural effusions (A). Lytic lesions at the lumbar spine, hepatomegaly and a large left adnexal cystic lesion were also noted (B).

Figure 4

Four-chamber view (A) with the corresponding longitudinal strain map showing reduced global longitudinal strain at −5.3% and apical sparing (>2:1 apical to basal ratio or ‘cherry on top’) pattern (B). 4CH; four chamber view, FR; frame rate, fps; frames per second, HR; heart rate, GS; global strain.

Figure 5

Histopathological images of the abdominal wall fat pad excision biopsy showing amyloid deposits near the interstitial and vascular structures seen on H&E staining (A) and supported by typical apple-green birefringence from Congo red staining (B), confirming the diagnosis of AL amyloidosis.

Video 1 Transthoracic echocardiogram video of representative apical four-chamber view showing decreased left ventricular ejection fraction of 43%, global hypokinesis and significantly thickened myocardium.

Differential diagnosis

Given her prior presentations suggestive of a diagnosis of HFpEF and her fluid overload status, the top differential diagnosis on arrival was acute on chronic heart failure exacerbation.


At the emergency department, the patient received diuresis with intravenous furosemide and was anticoagulated with a heparin drip given her subtherapeutic INR. She was admitted to telemetry with a diagnosis of volume overload and acute decompensation of chronic heart failure. Once the SPEP resulted positive, the initial plan was for her to undergo plasma exchange, but the patient’s overall condition rapidly deteriorated. She developed persistent hypotension, worsening oliguric renal failure and lactic acidosis and she was transferred to the cardiac critical care unit for haemodynamic support with dobutamine drip, vasopressors and haemodialysis. Of note, records showed that the patient was scheduled for a left heart catheterisation given the results of a recent stress echocardiogram 2 months before admission showing global hypokinesis, worst in the distal anteroseptal and the basal inferolateral walls. However, the patient was lost to follow-up at that time as well. As mentioned, given the clinical suspicion of AL amyloidosis, a fat pad biopsy was obtained and a diagnosis of plasma cell dyscrasia and new-onset MM was confirmed in the setting of recurrent SCC. The patient continued to deteriorate clinically. Although her prognosis was deemed poor, she was started on palliative treatment for her newly diagnosed plasma cell malignancy with bortezomib and dexamethasone. From the perspective of her recurrent SCC vulvar carcinoma, the patient was considered a poor candidate for immunotherapy or cytotoxic chemotherapy given her poor clinical condition and performance functional status.

Outcome and follow-up

Unfortunately, the patient did not respond to further treatment and opted to be discharged home on hospice for end-of-life supportive care.


CA remains a disease that demands further clinical attention for early diagnosis. Studies have shown that amyloid cardiomyopathy may be under-recognised in many patients diagnosed with heart failure, leading to substantial delays in diagnosis.11 This is particularly important given the short median survival time after diagnosis, as short as 6 months, from the onset of heart failure in AL amyloidosis.5–8 The challenge in identifying CA is mainly due to the non-specific clinical findings during the initial stages of the disease. Furthermore, the initial laboratory and cardiac imaging features overlap with those seen in patients with heart failure, especially HFpEF. An autopsy study of patients diagnosed with HFpEF showed amyloid deposition in 5%–12% of cases, depending on disease severity.12 Without a high index of suspicion for CA, clinicians could miss opportunities for early diagnosis and prevention of disease progression.

The onset of our patient’s disease and the timing of clinical and imaging findings are consistent with other cases documented in the literature. Even though she had imaging findings suggestive of amyloidosis, such as concentric LVH, decreased GLS with relative apical sparing (‘cherry on top’ appearance) and an ECG with low-voltage QRS, these findings were discovered towards the end of her disease progression. Low-voltage QRS was not found on any ECGs until 1 month before her final diagnosis of CA. However, data have shown that less than 40% of patients with biopsy-proven CA have low voltages on ECG even with advanced disease.13 Although the percentage of patients with AL amyloid who have a reduction in GLS is unknown, it has been reported to be one of the earliest markers of CA. The characteristic ‘cherry on top’ appearance was found to be 93% sensitive and 82% specific in identifying CA, which suggests that the utility of GLS values and patterns is beneficial in the diagnosis.14 However, this may be equally detrimental in cases where CA is prematurely or inappropriately ruled out in the absence of typical findings.

Our case is also unique because it provides insight not only into the diagnosis of CA in the setting of a malignancy but also into the impact of social context on patient outcomes. In a recent study, patients hospitalised for heart failure with amyloidosis as a secondary diagnosis were more likely to have underlying malignancy compared with those with heart failure without amyloidosis.15 Furthermore, patients from under-represented and lower socioeconomic groups may be at a disadvantage regarding the early diagnosis of AL amyloidosis due to factors such as lack of access to care, missed follow-ups and non-adherence to medical treatments. This is particularly important in CA because the average patient is diagnosed over 1 year after initial symptom onset, with approximately 33% of all patients having to visit five or more physicians before being officially diagnosed.5 The relevance of social context in patient outcomes is highlighted in our case. The patient had access to medical care through health insurance and support social services with Medicaid coverage. However, her long-standing substance use disorder interfered with her medical care, given that in the last year leading up to the diagnosis of CA she was lost to follow-up for her many cardiology, oncology, and primary care appointments. The patient also self-reported being inconsistent in taking her medications while continuing to use opioids. In these situations, given the patient’s social context, it is important to remember how an unconscious bias may limit differential diagnoses. For example, while it is possible that the patient’s recurrent dyspnoea was associated with medication non-adherence, it still would not have ruled out other aetiologies nor account for the findings related to progression of her underlying CA. One recent study analysing the data of patients with amyloidosis between 1990 and 2020 showed that non-Hispanic black individuals were likely to have more aggressive disease phenotypes and higher-risk sociodemographic factors, leading to a 24% higher age-adjusted and sex-adjusted hazard for mortality. Interestingly, the same study showed that race or ethnicity did not play a role in survival after controlling for disease severity and treatment.16 Another explanation for delayed diagnosis and worse outcomes in patients with amyloidosis may be the presence of other comorbidities. As supported by our case report, HPV has been associated with both SCC and plasma cell dyscrasias such as MM, with some studies even showing the presence of HPV sequences in bone marrow samples of patients.17 18 Studies have also shown that both HPV-associated malignancies and MM are more prevalent in patients with social issues and lower economic status.19 20 Our case shows the importance of having a high clinical suspicion for an early diagnosis of CA. It also highlights the importance of considering the influence of comorbidities and the socioeconomic factors related to this diagnosis.

Learning points

  • Cardiac amyloidosis (CA) is an under-recognised cause of heart failure in adults.

  • Prompt recognition is essential to improve patient outcomes; however, non-specific clinical disease manifestations pose a significant challenge in early diagnosis.

  • Characteristic findings of CA such as discordant LVH with low-voltage QRS and an TTE images of GLS with apical sparing can strongly suggest the disease; however, these features may not be present until the later stages of the disease and their absence should not rule out the diagnosis of CA.

  • Comorbidities and social factors can influence the diagnosis of CA and patient outcomes.

Ethics statements

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  • Twitter @GiselleSA_MDPhD

  • Contributors GAS-A contributed to the care of the patient and drafted and revised the initial manuscript. PL reviewed the literature and contributed to manuscript draft. BP and RT contributed to the care of the patient and to the revision of the manuscript. All authors approved the final version of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.