Amyloidosis of the gastrointestinal tract: a 13-year, single-center, referral experience.

Amyloidosis of the gastrointestinal tract, with biopsy-proven disease, is rare. We reviewed a series of patients who presented with biopsy-proven gastrointestinal amyloidosis and report their clinical characteristics, treatments, and survival. This is a retrospective review of data prospectively collected from January 1998 to December 2011 in a tertiary referral center; 2,334 patients with all types of amyloidosis were evaluated during this period. Seventy-six patients (3.2%) had biopsy-proven amyloid involvement of the gastrointestinal tract. Their median age was 61 years (range, 34-79). Systemic amyloidosis with dominant gastrointestinal involvement was present in 60 (79%) patients, whereas the other 16 (21%) patients had amyloidosis localized to the gastrointestinal tract without evidence of an associated plasma cell dyscrasia or other organ involvement. Of the 60 systemic cases, 50 (83%) had immunoglobulin light-chain, five (8%) had familial lysozyme, three (5%) had wild-type transthyretin, and two (3%) had mutant transthyretin amyloidosis. The most frequent symptoms for all patients were weight loss in 33 (45%) and gastrointestinal bleeding in 27 (36%). Incidental identification of amyloidosis on routine endoscopic surveillance played a role in the diagnosis of seven patients with systemic immunoglobulin light-chain, and four patients with immunoglobulin light-chain localized to the gastrointestinal tract. Amyloid protein subtyping was performed in 12 of the cases of localized disease, and all had lambda light chain disease. Of the 50 patients with systemic immunoglobulin light-chain amyloidosis, 45 were treated with anti-plasma cell therapy. The median survival has not been reached for this group. For the 16 patients with localized gastrointestinal amyloidosis, supportive care was the mainstay of treatment; none received anti-plasma cell therapy. All 16 are alive at a median follow-up of 36 months (range, 1-143). Patients with biopsy-proven gastrointestinal amyloidosis often present with weight loss and bleeding. In localized cases, all that underwent typing were due to lambda light chain amyloidosis and none progressed to systemic disease during the period of follow-up. Most patients with systemic disease had immunoglobulin light-chain, and their tolerance of therapy and median survival were excellent. Although a rare manifestation of amyloidosis, staining for amyloid should be considered in patients undergoing gastrointestinal biopsy who have unexplained chronic gastrointestinal symptoms.

Increased PEA3/E1AF and decreased Net/Elk-3, both ETS proteins, characterize human NSCLC progression and regulate caveolin-1 transcription in Calu-1 and NCI-H23 NSCLC cell lines.

Caveolin-1 protein has been called a 'conditional tumor suppressor' because it can either suppress or enhance tumor progression depending on cellular context. Caveolin-1 levels are dynamic in non-small-cell lung cancer, with increased levels in metastatic tumor cells. We have shown previously that transactivation of an erythroblastosis virus-transforming sequence (ETS) cis-element enhances caveolin-1 expression in a murine lung epithelial cell line. Based on high sequence homology between the murine and human caveolin-1 promoters, we proposed that ETS proteins might regulate caveolin-1 expression in human lung tumorigenesis. We confirm that caveolin-1 is not detected in well-differentiated primary lung tumors. Polyoma virus enhancer activator 3 (PEA3), a pro-metastatic ETS protein in breast cancer, is expressed at low levels in well-differentiated tumors and high levels in poorly differentiated tumors. Conversely, Net, a known ETS repressor, is expressed at high levels in the nucleus of well-differentiated primary tumor cells. In tumor cells in metastatic lymph node sites, caveolin-1 and PEA3 are highly expressed, whereas Net is now expressed in the cytoplasm. We studied transcriptional regulation of caveolin-1 in two human lung cancer cell lines, Calu-1 (high caveolin-1 expressing) and NCI-H23 (low caveolin-1 expressing). Chromatin immunoprecipitation-binding assays and small interfering RNA experiments show that PEA3 is a transcriptional activator in Calu-1 cells and that Net is a transcriptional repressor in NCI-H23 cells. These results suggest that Net may suppress caveolin-1 transcription in primary lung tumors and that PEA3 may activate caveolin-1 transcription in metastatic lymph nodes.

Metastatic interdigitating dendritic cell sarcoma masquerading as a skin primary tumor: a case report and review of the literature.

We report an unusual case of a lymph node interdigitating dendritic cell sarcoma (IDCS), metastatic to skin, in a 73-year-old patient. The patient initially presented as having a primary skin tumor with lymph node metastasis. The metastatic IDCS was initially read as an atypical fibroxanthoma. However, the morphology seen on the lymph node excision, paired with immunohistochemistry and electron microscopy studies, was diagnostic for an IDCS. Additional immunohistochemistry was performed on the shave biopsy, confirming that the skin tumor was a metastasis. IDCS is a rare tumor that belongs to the histiocytic and dendritic cell group of tumors. Diagnosing this entity is difficult without the aid of ancillary testing such as immunohistochemistry and electron microscopy. In the workup of a spindle cell neoplasm, IDCS should be included in the differential diagnosis.

Unusual tumor response and toxicity from radiation and concurrent erlotinib for non-small-cell lung cancer.

We report a case of a never-smoker female with non-small-cell lung cancer (NSCLC) who experienced a striking tumor response to combined low-dose radiation and the epidermal growth factor receptor inhibitor erlotinib, even though erlotinib alone was not effective in preventing tumor progression. Furthermore, the patient developed symptomatic pneumonitis, which is unusual for the small volume of lung that was exposed to a significant dose of radiation. This case demonstrates that combination therapy with radiation and erlotinib has the potential to significantly benefit a subset of patients with NSCLC in addition to those approximately 10% who have tumors which respond to erlotinib alone. It also highlights the potential risks of molecular targeted radiation therapy.

ETS1 regulates Twist1 transcription in a KrasG12D/Lkb1-/- metastatic lung tumor model of non-small cell lung cancer.

Distinct members of the Ets family of transcription factors act as positive or negative regulators of genes involved in cellular proliferation, development, and tumorigenesis. In human lung cancer, increased ETS1 expression is associated with poor prognosis and metastasis. We tested whether ETS1 contributes to lung tumorigenesis by binding to Twist1, a gene involved in tumor cell motility and dissemination. We used a mouse lung cancer model with metastasis driven by conditionally activated Kras and concurrent tumor suppressor Lkb1 loss (KrasG12D/ Lkb1-/- model) and a similar model of lung cancer that does not metastasize, driven by conditionally activated Kras alone (KrasG12D model). We show that Ets1 and Twist1 gene expression differs between KrasG12D tumors (low Ets1 and Twist1 expression) and KrasG12D/Lkb1-/- tumors (high Ets1 and Twist1 expression). In human lung tumors, ETS1 and TWIST1 expression positively correlates and low combined ETS1 and TWIST1 levels are associated with improved survival compared to high levels. Using mouse cell lines derived from KrasG12D and KrasG12D/Lkb1-/- mouse models and the human lung cancer (A549) cell line, we show that ETS1 regulates Twist1 expression. Chromatin immunoprecipitation assays confirm binding of ETS1 to the Twist1 promoter. Overexpression studies show that ETS1 transactivates Twist1 promoter activity in mouse and human cells. Silencing endogenous Ets1 by siRNA in mouse cell lines decreases Twist1 mRNA levels, decreases invasion, and increases cell growth. Ets1 and Twist1 are at the crossroad of several signaling pathways in cancer. Understanding their regulation may inform the development of therapies to impair lung tumor metastasis.

Endotracheal hamartoma case report: Two contrasting clinical presentations of a rare entity.

INTRODUCTION: The majority of tracheal tumors in adults are malignant. The finding of a benign tumor in the trachea is uncommon and endotracheal hamartomas are rare. PRESENTATION OF CASE: We report two cases presenting within six months at our institution. The first patient is a 67 year-old man who was found to have an asymptomatic endotracheal hamartoma on chest imaging for aortic valve replacement. The second patient is a 46 year-old man with an extensive continued tobacco use disorder and a known endotracheal lesion identified 8 years prior to intervention. Both patients were treated surgically and recovered without complications. DISCUSSION: Identification of these lesions and timely management are necessary because without intervention, they can lead to fatal complications. Most symptoms of tracheal hamartoma result from mechanical obstruction with the earliest presenting symptom being dyspnea, but as evident in these two cases, they can have different presentations. CONCLUSION: We have found that endotracheal hamartoma has a tendency to present in Caucasian, male patients with a comorbidity of respiratory disease and variable smoking history, but it can also present in asymptomatic patients with no significant smoking history.

Transbronchial biopsies safely diagnose amyloid lung disease.

BACKGROUND: Autopsy identifies lung involvement in 58-92% of patients with the most prevalent forms of systemic amyloidoses. In the absence of lung biopsies, amyloid lung disease often goes unrecognized. Report of a death following transbronchial biopsies in a patient with systemic amyloidosis cautioned against the procedure in this patient cohort. We reviewed our experience with transbronchial biopsies in patients with amyloidosis to determine the safety and utility of bronchoscopic lung biopsies. METHODS: We identified patients referred to the Amyloidosis Center at Boston Medical Center with lung amyloidosis diagnosed by transbronchial lung biopsies (TBBX). Amyloid typing was determined by immunohistochemistry or mass spectrometry. Standard end organ assessments, including pulmonary function test (PFT) and chest tomography (CT) imaging, and extra-thoracic biopsies established the extent of disease. RESULTS: Twenty-five (21.7%) of 115 patients with lung amyloidosis were diagnosed by TBBX. PFT classified 33.3% with restrictive physiology, 28.6% with obstructive disease, and 9.5% mixed physiology; 9.5% exhibited isolated diffusion defects while 19% had normal pulmonary testing. Two view chest or CT imaging identified focal opacities in 52% of cases and diffuse interstitial disease in 48%. Amyloid type and disease extent included 68% systemic AL disease, 16% localized (lung limited) AL disease, 12% ATTR disease, and 4% AA amyloidosis. Fluoroscopy was not used during biopsy. No procedure complications were reported. CONCLUSIONS: Our case series of 25 patients supports the use of bronchoscopic transbronchial biopsies for diagnosis of parenchymal lung amyloidosis. Normal PFTs do not rule out the histologic presence of amyloid lung disease.

miRNA profiling of primary lung and head and neck squamous cell carcinomas: Addressing a diagnostic dilemma.

OBJECTIVE: To determine whether microRNA (miRNA) profiling of primary lung and head and neck squamous cell carcinomas could be useful to identify a specific miRNA signature that can be used to further discriminate between primary lung squamous carcinomas and metastatic lesions in patients with a history of head and neck squamous cell cancer. METHODS: Specimens of resected primary head and neck and lung squamous cell carcinomas were obtained from formalin-fixed, paraffin-embedded blocks. Paraffin blocks were sectioned and deparaffinized, and total RNA was isolated and profiled. Quantitative polymerase chain reaction was performed to verify array results. RESULTS: Twelve head and neck and 16 lung squamous cell carcinoma samples met quality control metrics and were included for analysis. Forty-eight miRNAs were differentially expressed (P < .05) between the 2 groups. Of these, 30 were also significantly associated (q < .25) with tumor type in 2 independent sets of primary head and neck and lung squamous carcinomas profiled by The Cancer Genome Atlas consortium, including miR-34a and miR-10a. The ratio of miR-10a and miR-10b was especially predictive of primary cancer site in all 3 data sets, with area under the (receiver operating characteristics) curve values ranging from 0.922 to 0.982. Quantitative polymerase chain reaction confirmed the association of miR-34a expression and the miR-10:miR-10b ratio with tumor type. CONCLUSIONS: MicroRNA expression may be useful for discriminating between head and neck and lung squamous cell carcinomas, including miR-34a and the miR-10a:miR-10b ratio. This differentiation has clinical importance because it could help determine the appropriate therapeutic approach.

Surgical Management of Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma Associated With Light-Chain Deposition Disease.

A 52-year-old woman presented with a right middle lobe (RML) lung nodule suspicious for malignancy. Thoracoscopic middle lobectomy was performed. The pathology report revealed a pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma in association with light-chain deposition disease (LCDD). Pulmonary MALT lymphoma and LCDD are unusual disorders presenting in the lung, and the association between these 2 conditions is even more uncommon. The optimal management for these patients is controversial, although surgical resection of localized well-circumscribed lesions may represent an effective therapeutic approach.

Extranodal Marginal Zone Endobronchial Lymphoma Associated With Hepatitis C.

We describe two patients with hepatitis C and a diagnosis of pulmonary extranodal marginal zone B cell lymphoma. Both patients demonstrated a chronic nonproductive cough without hemoptysis. Diagnosis was obtained after a computed tomographic chest scan and flexible bronchoscopic biopsy. We discuss the staging and prognosis of this disease, its correlation with hepatitis C, and potential benefits of treating the associated hepatitis C.

Bone marrow core biopsy specimens in AL (primary) amyloidosis. A morphologic and immunohistochemical study of 100 cases.

We retrospectively reviewed 100 bone marrow core biopsy specimens from patients with AL (primary) amyloidosis. The morphologic and immunohistochemical features were assessed by standard histochemical stains (H&E, periodic acid-Schiff, Congo red) and immunohistochemical stains for light chain immunoglobulins. Bone marrow core biopsy revealed a plasma cell dyscrasia in 83% (lambda, 65; kappa, 18) of cases. Amyloid deposits were observed in 60% of the bone marrow core biopsy specimens and, when present, were detected most often in blood vessel walls only (39/60). However, if present, interstitial amyloid deposition was significantly more associated with patients with a monoclonal kappa light chain gammopathy (P = .04). Through the careful analysis of standard histochemical and immunohistochemical stains, bone marrow core biopsy provides essential diagnostic information in cases of AL amyloidosis.

Gamma heavy chain disease in a patient with underlying lymphoplasmacytic lymphoma of the thyroid. Report of a case and comparison with other reported cases with thyroid involvement.

BACKGROUND: Gamma heavy chain disease with underlying thyroid pathology is rare. There are 5 reported cases in the English literature, including the present case of an elderly female with γ heavy chain disease with underlying lymphoplasmacytic lymphoma of the thyroid who initially presented with long-standing goiter and chronic thyroiditis. METHODS: The protein studies and histopathologic findings in her thyroid are described. Her case is compared with reported cases of γ heavy chain disease with thyroid involvement. RESULTS: Initial impression on most cases was chronic thyroiditis; however pathology showed 3 cases with plasmacytoma and 2 with lymphoplasmacytic infiltrate. All were diagnosed and followed up using serum and urine electrophoresis. CONCLUSION: Gamma heavy chain disease has a protean manifestation; however there appears to be a more uniform pattern of the disease when it is associated with the thyroid. The inclusion of protein studies in cases diagnosed with chronic thyroiditis by FNA may aid in establishing γ heavy chain disease with underlying thyroid involvement. In this case serum and urine electrophoresis, and immunofixation studies which are simple and affordable tests facilitated the hematologic workup and follow up.

Dysregulation of miRNAs in AL amyloidosis.

Bone marrow plasma cells (BMPCs) were purified using anti-CD138 immunomagnetic beads, from aspirates obtained with permission of the Boston University Medical Campus Institutional Review Board, from patients with immunoglobulin light chain (AL) amyloidosis and from controls. Expression levels of MicroRNAs (miRNAs) were compared by microarray; 10 were found to be increased more than 1.5-fold. These results were confirmed using stem-loop RT-qPCR for the most highly upregulated miRNAs, miR-148a, miR-26a, and miR-16. miR-16, a micro-RNA linked to other hematopoietic diseases, was significantly increased in the AL group at diagnosis, and also in treated patients with persistent monoclonal plasma cells in the bone marrow, but not in patients who achieved a hematologic remission after therapy. miR-16 can be derived from the miR-16-1/mirR-15, a cluster on chromosome 13 or the miR-16-2/miR-15b cluster on chromosome 3. The expression of miR-15b was much higher than miR-15a in both AL and control BMPC, suggesting that miR-16 in plasma cells is mainly derived from miR-16-2/miR-15b. The anti-apoptosis gene BCL-2, a putative target mRNA that can be downregulated by miR-16, was expressed in BMPCs from AL patients, despite elevated levels of miR-16. Our data suggests that miRNAs are dysregulated in clonal plasma cells in AL amyloidosis and may be potentially useful as biomarkers of disease.

Matrix metalloproteinases and their tissue inhibitors in cardiac amyloidosis: relationship to structural, functional myocardial changes and to light chain amyloid deposition.

BACKGROUND: Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix disruption. Amyloid cardiomyopathy due to immunoglobulin light chain protein (AL-CMP) deposition has an accelerated clinical course and a worse prognosis compared with non-light chain cardiac amyloidoses (ie, forms associated with wild-type or mutated transthyretin [TTR]). We therefore tested the hypothesis that determinants of proteolytic activity of the extracellular matrix, the matrix metalloproteinases (MMPs), and their tissue inhibitors (TIMPs) would have distinct patterns and contribute to the pathogenesis of AL-CMP versus TTR-related amyloidosis. METHODS AND RESULTS: We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with TTR-associated forms of cardiac amyloidosis, ie, senile systemic amyloidosis (involving wild-type TTR) or mutant TTR, and 10 patients with AL amyloidosis without cardiac involvement. Serum MMP-2 and -9, TIMP-1, -2, and -4, brain natriuretic peptide values, and echocardiography were determined. AL-CMP and TTR-related amyloidosis groups had similar degrees of increased left ventricular wall thickness. However, brain natriuretic peptide, MMP-9, and TIMP-1 levels were distinctly elevated accompanied by marked diastolic dysfunction in the AL-CMP group versus no or minimal increases in the TTR-related amyloidosis group. Brain natriuretic peptide, MMPs, and TIMPs were not correlated with the degree of left ventricular wall thickness but were correlated to each other and to measures of diastolic dysfunction. Immunostaining of human endomyocardial biopsies showed diffuse expression of MMP-9 and TIMP-1 in AL-CMP and limited expression in TTR-related amyloidosis hearts. CONCLUSIONS: Despite comparable left ventricular wall thickness with TTR-related cardiac amyloidosis, AL-CMP patients have higher brain natriuretic peptide, MMPs, and TIMPs, which correlated with diastolic dysfunction. These findings suggest a relationship between light chains and extracellular matrix proteolytic activation that may play an important role in the functional and clinical manifestations of AL-CMP, distinct from the other non-light chain cardiac amyloidoses.