Pulmonary masses in a patient with dyspnea: Apply Occam's razor or Hickam's dictum?
Authors: Nelson Leung, Martha Grogan, Geoffrey B. Johnson, Mary E. Klecka, Angela Dispenzeiri
Journal: American Journal of Hematology (2014)

A 74-year-old white male, lifetime nonsmoker underwent evaluation for a 3 year history of dyspnea. Patient was a former professional athlete who was still working full time. He had remained physically fit and was able to perform his regular exercise routine which included 25 min on the elliptical machine plus weights. However, he would develop dyspnea when he walked up inclines/ramps or if there was a temperature change. Cardiac workup was negative. Cardiac computed tomography (CT) showed a coronary calcium score of zero. Exercise myocardial perfusion test showed a left ventricular ejection fraction (LVEF) of 59% at rest and 55% at peak exercise with no perfusion defects. Echocardiogram showed normal left ventricular size but mild hyperdynamic function of 71%. Pulmonary function test was normal with an FEV1 of 2.62 (112% predicted), diffusing capacity of the lung for carbon monoxide (DLCO) of 99% predicted and VO2 max of 20 ml/min/kg (96% predicted). Chest CT revealed pulmonary nodules in the right upper and lower lobes which were previously present on prior chest X-rays. A transbronchial biopsy of the lower nodule lesion found amorphous material within the alveolar septae. Congo red stain was positive for amyloid. Immunohistochemistry studies were focally positive for immunoglobulin kappa light chain, focally positive for lambda light chain and diffusely positive for transthyretin. Patient was given the diagnosis of transthyretin amyloidosis (ATTR) and was recommended to undergo testing for heart and liver transplantation. He presented for second opinion. Amyloidosis is a group of diseases resulting from misfolding of proteins 1. Transthyretin (aka prealbumin) is a protein carrier of thyroxine and retinol-binding protein bound to retinol which is made predominantly in the liver. Currently, two types of ATTR are recognized. The most common is the wild type (ATTRwt) also known as “senile ATTR” that occurs without any mutation. The true prevalence of ATTRwt is unknown as it is suspected to be markedly underdiagnosed. Most of these patients are male (88% in one series) and older (median age 73) 2. The most common presentation is dyspnea (>50%) with neuropathy present in <10% of cases. The other type is the hereditary form where a mutation in the transthyretin gene makes the protein amyloidogenic (ATTRm). Over a hundred mutations have been identified. Some mutations are associated with particular symptoms but other factors such as genetic, environmental, or epigenetic phenomenons can be influential as well 3. Age of presentation is more variable than with ATTRwt and can start as early as late teens. While it is still more common in males, it is less than that of ATTRwt. Neuropathy, which can be peripheral or central, is much more common in ATTRm. Cardiac and eye symptoms are frequent with some mutations. As 90% of the transthyretin is manufactured in the liver, liver transplantation has been successfully used but promising drugs are currently undergoing clinical trial for this disease 4. In patients with severe cardiac involvement, heart transplant has been performed in conjunction with liver transplantation 5. The typing of the amyloid should be performed on every case 6. It is crucial because treatment is type specific. Since immunoglobulin light chain amyloidosis (AL) is the most rapidly lethal and most common type of amyloidosis in industrialized nations, it should always be ruled out 7. In our patient, the partial staining of immunoglobulin light chains on immunohistochemistry raises some doubt on the amyloid type. Furthermore, patients with ATTR typically present with thicker cardiac septum than those of AL. With his “normal” echocardiographic findings from the outside, it is even more imperative to rule out AL as a cause. Evaluation at our center included a complete blood count which was normal. Serum protein electrophoresis revealed a monoclonal IgG lambda with an M-spike of 1.0 g/dl. A monoclonal IgG lambda fragment was also found in the urine but was not quantifiable. Serum free light chain assay showed a kappa of 1.07 mg/dl, lambda of 4.03 mg/dl and a ratio of 0.2655. The identification of the monoclonal IgG lambda makes ruling out AL even more imperative 8. Conversely, it should not be assumed that every patient with amyloid and a monoclonal gammopathy has AL. Epidemiologic studies suggest the prevalence of monoclonal gammopathy is as high as 5.6% in men our patient's age 9. In majority of these patients, the monoclonal gammopathy is a monoclonal gammopathy of undetermined significance (MGUS) which is by definition benign but possesses the risk of transforming to a more serious condition with time. Indeed, patients with hereditary amyloidoses and MGUS where the monoclonal protein is not related to the amyloid have been reported 10. Due to the presence of the monoclonal protein, a bone marrow biopsy was performed. A lambda light chain restricted plasma cells population was identified representing <5% of the cellularity. In addition, there was a population of predominantly interstitial and focally intrasinusoidal CD20 positive B-cells coexpressing kappa light chain, DBA44, TCL1A, CD123, and CD25. Cyclin D1 appeared negative. Annexin was difficult to interpret and tartrate-resistant acid phosphatase (TRAP) was not positive. Scattered small T-cells were also present. Stain for amyloid was negative on the bone marrow although only a few vessels were present in the sample. The amyloid from his lung was typed using liquid chromatography tandem mass spectrometry. A wild type transthyretin protein was identified. Amyloid typing by laser microdissection followed by proteomics by liquid chromatography tandem mass spectrometry has become the gold standard in amyloid typing 11. Although sensitivity and specificity are both superior to immunohistochemistry, its biggest advantage is its efficiency 6. With immunohistochemistry, each type of amyloid must be tested individually, but proteomic analysis by mass spectrometry can all be done in a one step process. Our testing confirmed the type of amyloid to be ATTRwt. No abnormal transthyretin was identified using mass spectrometry of his serum further supporting the wild type ATTR. The monoclonal IgG lambda in this case appeared to be a MGUS. This case emphasizes the importance of accurately typing of the amyloid as the assumption that a monoclonal immunoglobulin plus amyloid equal AL has resulted in patients inappropriately receiving cytotoxic therapy for hereditary amyloidosis 10. Incidentally, a low grade B-cell lymphoproliferative disorder was identified which only requires observation at this time. Once the amyloid was typed, the focus was turned toward assessment of organ involvement which has a large impact on the overall prognosis and treatment. Electrocardiogram (ECG) showed normal sinus rhythm with T-wave abnormality. Echocardiogram showed a LVEF of 71% with normal left ventricular size but a basal septal wall thickness of 17 mm. Global strain was −15% (normal is <−18%). Cardiac troponin T was abnormal at 0.01 ng/ml (normal is <0.01 ng/ml) and N-terminal pro brain naturietic peptide was elevated at 969 pg/ml (normal is <173 pg/ml). Creatinine was normal at 1.2 mg/dl. Urine protein excretion was normal at 45 mg/d. Liver function test were within normal limits and patient had no neuropathic symptoms. Organ assessment showed the liver and kidney were not clinically involved. Patients exhibited no neurologic symptoms, most notably no carpal tunnel symptoms. Other than the amyloidoma in the lung, the heart seems to be the only other organ involved. The echocardiogram was inconclusive as the strain was abnormal but only the basal septal wall was thickened, which could be age-related or due to hypertensive heart disease rather than amyloidosis. Amyloidosis most commonly causes diffuse wall thickening. ECG did not meet criteria for low voltage, although low voltage is less common in ATTR than in AL. Cardiac biomarkers were elevated but these are nonspecific for amyloidosis. Strain rate measurement has significantly increased the sensitivity of echocardiogram in the diagnosis of cardiac amyloidosis. Abnormal strain rate can accurately diagnose cardiac involvement even when other echocardiographic features of amyloidosis are absent 12. In our patient, further testing is required to demonstrate cardiac involvement of amyloidosis versus other cardiac diseases. A cardiac magnetic resonance imaging (MRI) was performed. This showed normal left ventricular size with mild to moderately increased left ventricular wall thickness. The maximal end-diastolic myocardial thickness = 18 mm at the basal septum. Cine inversion recovery (IR) images showed that the myocardium nulled at a similar time to the blood pool. Diffuse delayed myocardial enhancement was demonstrated, most pronounced involving the left ventricular apex where there was diffuse subendocardial enhancement (Fig. 1). LVEF was 61%. Diffuse right ventricular delayed enhancement was also noted in the right ventricle and systolic function was mildly reduced with right ventricular ejection fraction of 45%. A collage of images from a short axis cardiac MRI with contrast showed diffuse abnormal delayed enhancement of the left and right ventricular myocardium. The MRI also showed abnormal nulling of myocardium (not shown). These findings are strongly suggestive of cardiac amyloidosis. Cardiac MRI with gadolinium enhancement is another imaging study that can be helpful in the detection of amyloid involvement in the heart. When delayed postgadolinium enhancement and abnormal myocardial and blood pooled gadolinium kinetics are present, the sensitivity is 97% 13. The postgadolinium enhancement is classically diffuse but can be focal in ATTR 14. Despite the evidence of focal amyloid involvement in the heart, functional testing could not explain the degree of his dyspnea. Cardiology consultation was obtained who agreed the symptom could not be explained based on the limited cardiac involvement. The evaluation was then refocused back on the lung. A new review of the chest CT revealed a right upper lobe 3.2 × 2.3 cm nodule (Fig. 2), a right lower lobe 2.7 × 2 cm nodule, bilateral micronodularity and trace bilateral pleural effusions. The lower lobe lesion contained scattered calcifications and had an adjacent consolidative opacity extending medially which had increased in size when compared with an abdominal CT taken 43 months earlier but only slightly in the previous 9 months (Fig. 3). This was thought to be consistent with the diagnosis of amyloidoma. The upper lobe lesion had a part-solid appearance that was more concerning for a bronchogenic carcinoma. The mass was not present on a chest CT from 6 years earlier. As a result, an open lung biopsy was performed which showed an invasive moderately differentiated adenocarcinoma with acinar and lepidic predominant growth patterns. Margins were negative and there was no evidence of pleural or angiolymphatic invasion. Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation analyses were negative. Amorphous material was also found in the vessels and alveolar septae that was consistent with amyloid. Six months after the lung resection, patient had recovered from his surgery and his atypical dyspnea had resolved. A chest CT without contrast showed an irregular 3.2 × 2.3 cm part-solid nodule in the right upper lobe, which was not present on a CT from 6 years prior (not shown). These findings are highly worrisome for a primarily pulmonary adenocarcinoma. CTs of the chest without contrast demonstrated slowly progressive (Left to right panels) nodular opacities in the right lower lobe with scattered calcifications that later became confluent and extended medially. The opacities had minimally progressed from 9 months prior but had clearly progressed when compared with images from 43 to 62 months prior. The trace pleural effusion was new. For the lung cancer, serial chest CT scans are being performed. CT scan at 6 month post operatively was negative for any new changes. From his ATTRwt standpoint, follow up is mainly focused on his heart to look for progression. This is being performed by echocardiogram and cardiac biomarker 8. Monoclonal protein study should be performed every 6–12 months to monitor the plasma cell dyscrasia. The development of any kappa restricted monoclonal protein would suggest progression of the kappa light chain restricted B-cell clone. B-cell lymphoproliferative disorders have been reported to cause AL 15. In medicine, it is often impressed on us to use the fewest number of diagnoses to explain all of the symptoms. This comes from the principle of William of Occam which states that among competing hypotheses, the one with the fewest assumptions should be selected. More complex explanations are not necessarily incorrect but without convincing evidence, the fewer assumptions, the better. Unfortunately, the principle of Occam's razor does not always fit every situation. Here, we describe a case of ATTRwt in a patient with a plasma cell dyscrasia, low grade B-cell lymphoproliferative disorder and adenocarcinoma of the lung whose only symptom was atypical dyspnea. To the best of our knowledge, this is the first case where ATTR coexisted with a lung cancer. Studies have found a low preoperative transthyretin level is associated with early recurrence in nonsmall cell lung cancer but the transthyretin level does not correlate with staging of the cancer 16. The dyspnea could have easily been attributed to the cardiac involvement if not for all the inconsistencies. By going through the evaluation step by step, three additional diagnoses were discovered. While the fate of two remains to be determined, the third turned out to be one of the more serious of the four diagnoses. This leads us to Dr. John Hickam's assertion that a diagnosis should not be excluded just because it does not fit the principle of Occam's razor. In fact, statistically it is more likely to have multiple common ailments than one rare disease that explains everything the patient is experiencing. At least this time, Hickam's dictum was the better approach than Occam's razor.