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59-Year-Old Man With Fatigue, Weight Loss, and Hepatomegaly

2018; Elsevier BV; Volume: 93; Issue: 10 Linguagem: Inglês

10.1016/j.mayocp.2017.12.028

1942-5546

Jacob J. Orme, Surbhi Sidana, Wilson I. Gonsalves,

Multiple Myeloma Research and Treatments

A 59-year-old man with type 2 diabetes, hypertension, and hyperlipidemia presented to his primary care physician with a 2-year history of fatigue and a 30-kg weight loss over a period of 6 months. His appetite remained stable, but he experienced early satiety. The patient reported no new joint or bone pains, light-headedness, dizziness, chest discomfort, or shortness of breath. He had never smoked, and his medications included glimepiride, labetalol, and simvastatin. His surgical history was notable for bilateral carpal tunnel release performed 5 years previously. He had no history of any recent travel. Family history was remarkable for type 2 diabetes and hyperlipidemia. Physical examination revealed a blood pressure of 136/87 mm Hg without orthostasis and a heart rate of 81 beats/min. He appeared fatigued, and his mouth examination revealed moist mucous membranes, with no ulcerations or macroglossia. The abdomen was mildly distended but not tender to palpation. Hepatosplenomegaly was noted, with the liver palpable 3 cm below the right costal margin and the spleen tip palpable 2 cm below the left costal margin. Findings on pulmonary, cardiovascular, and lymph node examinations were unremarkable. Computed tomography (CT) of the abdomen and pelvis confirmed the presence of hepatosplenomegaly and also revealed several partially calcified omental masses and periportal adenopathy.1.Which one of the following is the best course of action at this time?a.Imaging-guided biopsyb.Abdominal magnetic resonance imaging (MRI)c.Whole-body 2-deoxy-2-[18F]-fluorodeoxyglucose ([18F]-FDG) positron emission tomography/CTd.Stereotactic radiatione.Chemotherapy A patient with a history of substantial weight loss and the presence of multiple abdominal masses should raise suspicion for malignancy vs infection. Tissue confirmation of the underlying pathology is critical. Thus, imaging-guided biopsy of the omental mass is the best option at this time. Abdominal MRI may better characterize the extent of masses but will not provide definitive diagnosis. Similarly, whole-body [18F]-FDG positron emission tomography/CT will better characterize the extent of the disease process in the setting of high [18F]-FDG uptake by these masses; however, it will not provide a definitive diagnosis. Stereotactic radiation and chemotherapy are not appropriate at this time as no definitive tissue diagnosis has been obtained to warrant definitive treatment. Subsequent CT-guided biopsy of one of the omental masses revealed a light pink, amorphous, extracellular material on hematoxylin-eosin staining, with an apple-green birefringence on Congo red stain under polarized light. This staining pattern is characteristic of amyloid deposits and is produced by the mixture of negative (blue color) and positive (yellow color) birefringence of tangled amyloid fibrils that appear green. Although all amyloid fibrils have the same characteristic cross-β sheet quaternary structure that stains positive with Congo red, they can be comprised of various misfolded proteins whose underlying source determines the subtype classification.2.Which one of the following modalities will best determine the patient's subtype of amyloidosis?a.Immunohistochemistryb.Liquid chromatography tandem mass spectrometryc.Thioflavin T staind.Transthyretin (TTR) genotypinge.Hematoxylin-eosin staining Immunohistochemistry using immunoperoxidase staining of formalin-fixed, paraffin-embedded tissue was typically used before the advent of LMD-MS but is less sensitive and specific than newer methods.1Gilbertson J.A. Theis J.D. Vrana J.A. et al.A comparison of immunohistochemistry and mass spectrometry for determining the amyloid fibril protein from formalin-fixed biopsy tissue.J Clin Pathol. 2015; 68: 314-317Crossref PubMed Scopus (79) Google Scholar The criterion standard for amyloid subtyping is laser microdissection followed by mass spectrometry (LMD-MS). In brief, known amyloid deposits on a slide from a tissue biopsy are microdissected by laser microscopy. This dissected material containing the amyloid deposit is broken down by tryptic digestion, and the breakdown peptides are analyzed by liquid chromatography tandem mass spectrometry. The resultant spectrometric peak pattern of peptides can be compared to known peptide databases that confirm the amyloid subtype such as immunoglobulin light chain amyloidosis (AL) or immunoglobulin heavy chain amyloidosis, TTR amyloidosis, and leukocyte chemotactic factor 2 amyloidosis. Although Thioflavin T binds to the β sheet–rich structures of amyloid deposits, it is unable to differentiate subtypes of amyloidosis, much like Congo red. Genotyping of TTR should be performed only after a diagnosis of TTR amyloidosis is confirmed by mass spectrometry. Hematoxylin-eosin staining will not offer additional information regarding the patient's amyloidosis subtype. The LMD-MS results in this patient's biopsy specimen demonstrated a peptide profile consistent with AL λ-type amyloid deposition.3.Given the biopsy results, which one of the following diagnostic tests is most likely to be useful in this patient?a.QuantiFERON-TB Gold testb.Serum and urine protein electrophoresis (SPEP/UPEP) with immunofixation (IFE) and serum free light chain (sFLC) assayc.C-reactive proteind.β2-Microglobuline.Antinuclear antibody test The QuantiFERON-TB Gold test could be used to assess for tuberculosis, which has been commonly associated with the formation of AA-type amyloid deposits, but would not be the most useful option. Given the AL λ-type amyloid deposititions, the presence of a monoclonal gammopathy forming these amyloid deposits, and arising from either clonal plasma cells or B cells, must be suspected. Hence, a SPEP/UPEP with IFE should be performed in conjunction with an sFLC assay. The latter test is crucial because patients with AL amyloidosis may have a normal SPEP/UPEP result and even a normal IFE result despite the presence of clonal immunoglobulin free light chains in the serum. The C-reactive protein level may be elevated in various inflammatory or infectious conditions and is not specific to diagnosing an underlying monoclonal gammopathy. β2-Microglobulin is a serum protein commonly elevated in various hematologic diseases, especially monoclonal gammopathies. Although it may be abnormal in the patient in this case, similar to C-reactive protein, it is not specific for confirming the presence of a monoclonal gammopathy. If the LMD-MS results from the omental mass biopsy had demonstrated AA-type amyloid deposits, it could suggest the presence of a chronic inflammatory disease or chronic infection. In such a situation, the antinuclear antibody test can be performed to screen for chronic autoimmune diseases. The initial laboratory evaluation revealed the following (reference ranges provided parenthetically): SPEP with IFE revealed the presence of a 0.6-g/dL monoclonal IgG λ paraprotein; the κ sFLC was 1.78 mg/dL (0.33-1.94 mg/dL); λ sFLC was 16.7 mg/dL (0.57-2.63); and the serum free κ:λ ratio was 0.1 (0.26-1.65). A 24-hour urine protein assessment yielded 60 mg of protein, 8 mg of which were fragments of a monoclonal IgG λ paraprotein. No albuminuria was noted. A subsequent bone marrow biopsy revealed hypercellular bone marrow, with 60% cellularity and 8% λ-restricted plasma cells. Further laboratory evaluation revealed the following: hemoglobin, 11.3 g/dL (13.5-17.5 g/dL); platelet count, 983 × 109/L (150-450 × 109/L); white blood cell count, 9.2 × 109/L (3.5-10.5 × 109/L); ferritin, 92 μg/L (24-336 μg/L); creatinine, 1.1 mg/dL (0.8-1.3 mg/dL); alkaline phosphatase, 720 U/L (45-155 U/L); troponin T, 40 ng/L ( 95%) of yielding a diagnosis is the organ suspected of involvement based on clinical and laboratory assessments. However, less invasive sources such as bone marrow and fat aspiratation can yield sensitivity results of 65% and 80%, respectively, making them attractive alternatives to performing a biopsy on critical organs like the heart, kidney, or liver.2Gertz M.A. Buadi F.K. Zeldenrust S.R. Hayman S.R. Immunoglobulin light-chain amyloidosis (primary amyloidosis).in: Hoffman R.D. Benz Jr., E.J. Silberstein L.E. Heslop H.E. Weitz J.I. Anastasi J. Hematology: Basic Principles and Practice. 6th ed. Churchill Livingstone, London2013: 1350-1374Google Scholar It is not necessary to obtain more than one biopsy specimen containing AL amyloid deposits for the diagnosis of systemic AL amyloidosis.8Muchtar E. Dispenzieri A. Lacy M.Q. et al.Overuse of organ biopsies in immunoglobulin light chain amyloidosis (AL): the consequence of failure of early recognition.Ann Med. 2017; 49: 545-551https://doi.org/10.1080/07853890.2017.1304649Crossref PubMed Scopus (27) Google Scholar Subtyping of the amyloid deposits detected on tissue biopsy is critical for the management of patients because it allows confirmation of the amyloid precursor protein, thus aiding in treatment decisions. For example, treating a patient with mutant TTR amyloidosis with cytotoxic chemotherapy will provide no benefit. In such patients, the problem lies within the liver and is not related to clonal bone marrow plasma cells; rather, chemotherapy would only expose such patients to unwarranted adverse effects. The mainstay of therapy for systemic AL amyloidosis is to reduce the clonal plasma cell population responsible for the amyloidogenic immunoglobin fragments. This treatment can result in symptomatic improvement in the affected organs over a period of time and subsequently leads to improved survival. However, it is important to be aware that organ responses can lag behind hematologic responses by several months, as outlined in this case. This time lag should be considered when evaluating concerns of premature therapy failure. Traditionally, treatment has consisted of cytotoxic chemotherapy such as high-dose melphalan followed by stem cell rescue or less intense forms of chemotherapy such as alkylators, proteasome inhibitors, or immunomodulators. Newer treatment approaches, which are currently under investigation, include monoclonal antibodies directed against the CD38 antigen on plasma cells and novel agents directed at dissolving already deposited amyloid fibrils to improve organ function and limit early mortality.9Sher T. Fenton B. Akhtar A. Gertz M.A. First report of safety and efficacy of daratumumab in 2 cases of advanced immunoglobulin light chain amyloidosis.Blood. 2016; 128: 1987-1989Crossref PubMed Scopus (68) Google Scholar, 10Gertz M.A. Landau H. Comenzo R.L. et al.First-in-human phase I/II study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction.J Clin Oncol. 2016; 34: 1097-1103https://doi.org/10.1200/JCO.2015.63.6530Crossref PubMed Scopus (147) Google Scholar A recent cohort study found that early diagnosis and the availability of plasma cell–directed therapies improved mortality for patients with systemic AL amyloidosis treated with ASCT or with less intense chemotherapy.11Muchtar E. Gertz M.A. Kumar S.K. et al.Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death.Blood. 2017; 129: 2111-2119Crossref PubMed Scopus (209) Google Scholar This case highlights the progressive damage of infiltrating misfolded light chain protein that can occur in various organs. It stresses the importance of an early and accurate diagnosis because subsequent therapy can produce durable disease remission and improvement in the end-organ damage.