*From the Division of Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, IL.
Correspondence to: Won Y. Lee, MD, Division of Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, IL 60612; e-mail: Won_Lee@rush.edu
A 25-year-old man presented with diarrhea for 6 months, unintentional 20-pound weight loss, and upper-torso flushing when taking showers. Evaluation of diarrhea was nondiagnostic, including bacterial and parasitic stool cultures, celiac sprue serology, GI endoscopies with biopsies, and abdominal CT scan. Incidentally, CT of the chest revealed diffuse bilateral nodular opacities without adenopathy or pleural abnormalities (Fig 1
). On further questioning, the patient denied cough, dyspnea, hemoptysis, fever, or night sweats.
The patient was born in India but had lived in Chicago for the past 7 years. He was treated for malaria 10 years ago and was not taking medications. He smoked infrequently, denied illicit drug use or recent travel, and had no pets or occupational exposures.
BP, heart rate, temperature, and oxygen saturation were normal. He appeared thin with temporal wasting. His pulmonary examination was unremarkable, without crackles or wheezes. A grade II/VI systolic murmur was auscultated at the right sternal border. His abdomen was soft without organomegaly. He had no edema or clubbing.
CBC with differential, comprehensive metabolic panel, liver and thyroid studies, urinalysis, HIV antibody, erythrocyte sedimentation rate, and anti-nuclear antibody were all normal. Pulmonary function testing showed severe restriction; total lung capacity was 48% of predicted. The patient was unable to perform a breath hold to allow evaluation of diffusing capacity for carbon monoxide.
Flexible fiberoptic bronchoscopy revealed normal airways, and BAL samples showed no bacterial, viral, fungal, or mycobacterial pathogens. Microscopic examination of transbronchial biopsies showed acellular waxy eosinophilic deposits. When stained with Congo red and viewed under polarized light, the biopsy sample was diagnostic of pulmonary amyloidosis (Fig 2, 3
). Evaluation for associated systemic amyloid included a normal serum and urine immunoelectrophoresis, normal bone marrow biopsy, echocardiogram with normal systolic and diastolic function, and no amyloid on prior GI biopsies.
Careful re-examination of the hematoxylin-eosin–stained transbronchial biopsy specimens confirmed the presence of amyloid. However, also identified were atypical epithelioid and spindle-shaped cells (Fig 4
) suspicious for a low-grade neuroendocrine tumor, such as carcinoid or medullary thyroid carcinoma.
Evaluation for carcinoid revealed a normal urinary 5-hydroxyindoleacetic acid. However, tumor markers for medullary thyroid carcinoma were markedly elevated and included a serum calcitonin of 80,941 pg/mL (normal < 13 pg/mL) and carcinoembryonic antigen of 1,248 ng/mL (normal < 3 ng/mL). Ultrasound identified a 3 × 2-cm thyroid nodule that, when sampled by biopsy and analyzed by immunohistochemistry, confirmed the diagnosis of medullary thyroid carcinoma.
Amyloid consists of insoluble fibrillar proteins that aggregate in a twisted β-pleated sheet configuration. Microscopically, amyloid protein stains with Congo red and displays the pathognomonic apple-green birefringence when viewed under polarized light. All forms of amyloid share this similar proteinaceous structure yet are distinguished by the unique biochemical composition of its precursor fibril protein. On diagnosis of pulmonary amyloid, the clinician should perform a two-step evaluation: (1) assess for systemic amyloidosis; and (2) precisely identify the precursor fibril responsible for amyloid deposition. Both have important prognostic implications and will guide appropriate therapy.
Amyloid is diverse and can be localized or systemic, and deposition into tissue and organs may result in disruption of normal function. Amyloid limited to the respiratory tract usually portends a favorable prognosis and includes tracheobronchial lesions or solitary parenchymal nodules (amyloidomas). Alternatively, respiratory amyloid associated with systemic disease is associated with worsened survival, and the typical radiographic pattern is diffuse with interstitial and reticulonodular opacities.
Diagnosis by transbronchial biopsy raises the concern for bleeding secondary to amyloid vasculopathy, yet the series of patients with pulmonary amyloid described by Utz et al were associated with limited bleeding complications. Fortunately, our patient had no significant bleeding, yet clinicians considering pulmonary amyloid should still exercise careful precautions when performing diagnostic tissue sampling.
A diagnosis of respiratory amyloid should lead to evaluation for other organ involvement. A reasonable approach includes bone marrow evaluation, liver and kidney function testing, pulmonary function tests, radiographic imaging, and echocardiography. In our case, a search for systemic amyloid revealed no involvement of the bone marrow, heart, or GI tract.
Classification of amyloid depends on the precursor fibril protein. More than 20 different fibrils have been described, and treatment involves reducing the synthesis of the respective fibril. For example, amyloid light chain is associated with plasma- cell dyscrasias leading to Ig light-chain deposition, and treatment includes chemotherapy. Reactive secondary amyloid leading to serum amyloid A protein has been associated with familial Mediterranean fever, and treatment includes colchicine. Amyloid transthyretin is familial and may require liver transplantation. We describe a patient with metastatic medullary thyroid carcinoma with excessive calcitonin, resulting in respiratory amyloid, classified as amyloid calcitonin.
Medullary thyroid carcinoma is a neuroendocrine tumor of the C (parafollicular) cells of the thyroid gland. Medullary thyroid carcinoma exhibits unusual features, including its association with amyloid (reported in up to 90% of tissue samples), C-cell secretion of calcitonin, genetic pattern, and relationship with other neuroendocrine syndromes. The combined presence of amyloid and immunohistochemical staining for calcitonin are hallmark pathologic features of medullary thyroid carcinoma. Mass spectroscopy analysis of denatured amyloid from medullary thyroid carcinoma tissue confirms that calcitonin is the responsible precursor fibril. The hormonal effects of calcitonin can lead to diarrhea and flushing and was the reason for our patient's clinical symptoms.
The RET (rearranged during transfection) protooncogene is a tyrosine kinase receptor that has been implicated in the oncogenesis of medullary thyroid carcinoma. RET gene mutations have been associated with hereditary medullary thyroid carcinoma, medullary thyroid carcinoma associated with multiple endocrine neoplasia (MEN) syndromes (MEN IIA and MEN IIB), and sporadic medullary thyroid carcinoma. Therefore, patients with medullary thyroid carcinoma should undergo a germ-line RET analysis, which may identify at-risk first-degree relatives. Finally, because of its association with multiple endocrine neoplasia syndromes, pheochromocytoma, parathyroid adenoma, or neuromas should be evaluated.
Treatment of amyloid involves reducing the precursor fibril responsible for amyloid deposition. In our patient, the culprit fibril was excessive calcitonin secondary to metastatic medullary thyroid carcinoma. Medullary thyroid carcinoma is usually locally invasive, yet metastasis may occur to the liver, bones and, as demonstrated in our patient, the lungs. Localized disease may be treated surgically with thyroidectomy and modified central neck dissection, whereas metastatic disease requires chemotherapy. Patients with diarrhea and flushing may be treated symptomatically with somatostatin analogs such as octreotide.
Clinical evaluation revealed no associated MEN syndromes, and genetic testing for the RET protooncogene mutation was negative; therefore, a diagnosis of sporadic medullary thyroid carcinoma was made. The patient had stage 4 disease and was treated with doxorubicin and cisplatin, unfortunately without improvement of the tumor (calcitonin level remained > 80,000 pg/mL). His diarrhea partially responded to octreotide.
Our patient remains alive and will receive chemotherapy with vandetanib (ZD6474), a multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor and epidermal growth factor receptor, both involved in tumor angiogenesis. Importantly, vandetanib also inhibits RET tyrosine kinase, which may be particularly beneficial in the treatment of medullary thyroid carcinoma.
Amyloidosis localized to the respiratory system portends a favorable prognosis, whereas pulmonary amyloid associated with systemic involvement has a worsened mortality rate.
On diagnosis of pulmonary amyloid, the clinician should perform a thorough two-step evaluation: (1) assess for systemic amyloidosis, and (2) precisely identify the precursor fibril responsible for amyloid deposition. Both steps have important prognostic implications and will guide treatment.
An associated neoplasm should be considered in the differential diagnosis of pulmonary amyloidosis.
Metastatic medullary thyroid carcinoma leading to marked elevation of calcitonin is an uncommon cause of pulmonary amyloidosis.
The authors have no conflicts of interest to disclose.
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