Eunhee S. Yi

Keratinocyte Growth Factor Decreases Pulmonary Edema, Transforming Growth Factor-Beta and Platelet-Derived Growth Factor-BB Expression, and Alveolar Type II Cell Loss in Bleomycin-Induced Lung Injury

Keratinocyte growth factor (KGF), a potent growth factor for type II pneumocytes and Clara cells, has been shown to prevent the end-stage pulmonary fibrosis and mortality in a rat model of bleomycin-induced lung injury. In this study, protective effects of KGF were explored during the earlier course of bleomycin-induced lung injury by studying protein exudation in alveolar edema fluids, pulmonary expression of transforming growth factor-beta (TGFβ) and platelet-derived growth factor-BB (PDGF-BB), and changes in type II pneumocytes and Clara cells after i.t. (intratracheal) bleomycin injection following KGF- or saline-pretreatment in rats. Total protein in bronchoalveolar lavage (BAL) fluids after bleomycin injury from KGF-pretreated rats was significantly lower than the levels in saline-pretreated rats. TGFβ protein in BAL fluids which peaked at day 3 after i.t. bleomycin in saline-pretreated lungs was not significantly increased at any time points in KGF-pretreated rats. PDGF-BB protein in whole lung tissues of KGF-pretreated rats also remained near normal throughout the course after i.t. bleomycin, in contrast to the significant increase in saline-pretreated rats. Numbers of type II pneumocytes and Clara cells in KGF-pretreated lungs after a high dose of bleomycin were close to the normal in intact lungs. At the same dose of bleomycin injury, type II pneumocytes in saline-pretreated lungs were markedly decreased, while the number of Clara cells in these rats was relatively preserved as the pre-injury level. In conclusion, KGF prevents bleomycin-induced end-stage pulmonary injury and mortality probably at least partly by decreasing protein-rich pulmonary edema, protein expression of fibrogenic cytokines TGFβ and PDGF-BB, and type II cell loss during the course of lung injury.

Strong PDGFRA positivity is seen in GISTs but not in other intra-abdominal mesenchymal tumors: Immunohistochemical and mutational analyses.

Mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene has been well documented as an alternative oncogenic mechanism in a subset of gastrointestinal stromal tumors (GISTs) lacking c-kit mutations. However, the role of PDGFRA immunohistochemistry in the diagnosis of GISTs has not been well studied. We investigated PDGFRA immunoreactivity in GISTs and in other intra-abdominal mesenchymal tumors, and correlated PDGFRA expression with CD117 positivity and with the mutational status of PDGFRA and c-kit genes. In addition, expression of phosphorylated AKT, an activated downstream molecule in the PDGFRA and c-kit signaling pathways, was correlated with PDGFRA and CD117 status. A total of 39 GISTs and 20 other mesenchymal tumors in the abdomen were included in this study. Thirty-five of 39 GIST cases (89.7%) were positive for PDGFRA and 19 of these 35 positive cases were strongly positive. Five of 20 non-GIST lesions (25%) were positive for PDGFRA, but none of these cases were strongly positive. With one exception, PDGFRA-positive cases were also positive for CD117. Phosphorylated AKT positivity was not associated with the immunoreactivity or mutation of PDGFRA and c-kit, suggesting that the activation of AKT is probably independent of the activation of PDGFRA and c-kit in GISTs. Of 14 GISTs assayed, 4 had mutations in c-kit at exons 11 or 17, and 4 had mutations in PDGFRA at exons 12 or 18. Three of 4 GIST cases with PDGFRA mutations show epithelioid morphology and strong PDGFRA immunoreactivity with prominent perinuclear dotlike accentuation (so-called Golgi pattern). In conclusion, strong PDGFRA positivity with Golgi pattern is a useful adjunct in the diagnosis of GISTs with PDGFRA mutation.

Severe alveolar proteinosis following chemotherapy for acute myeloid leukemia in a lung allograft recipient

A 64-year-old man was diagnosed with acute myeloid leukemia (AML) 5 years following single lung transplantation performed for severe pulmonary hypertension from scleroderma. Chemotherapy for treatment of AML with fludarabine, cytosine arabinoside, G-CSF (FLAG) regimen was initiated. Despite intensive antibiotic treatment for a presumptive diagnosis of bacterial pneumonia, the patient developed acute respiratory failure and died before a complete cycle of chemotherapy could be administered. At autopsy, both native and allograft lungs showed widespread alveolar proteinosis that was determined as the main cause of acute respiratory failure. Alveolar proteinosis, a potentially treatable disease, should be considered in the radiologic differential diagnosis of diffuse lung disease in this clinical setting.

Endotracheal Castleman Disease: A Case Report

Castleman disease (CD) is an uncommon benign lymphoid hyperplasia with several clinical and morphologic variants associated with distinct outcomes. Pulmonary CD has been reported as a rare extranodal manifestation in the literature. However, CD presenting as an obstructive mass in the airway has not been documented. We report a case of localized hyaline-vascular CD presenting as an endotracheal lesion. The patient was a 50-year-old woman with Marfan syndrome. The lesion caused near-complete airway obstruction with respiratory insufficiency. The patient underwent laser resection, and the diagnosis of CD was supported by comprehensive studies including histopathologic, immunohistochemical, and molecular methods.

Congenital Pulmonary Airway Malformation (Congenital Cystic Adenomatoid Malformation) with Multiple Extrapulmonary Anomalies: Autopsy Report of a Fetus at 19 Weeks of Gestation

Congenital pulmonary airway malformation, or congenital cystic adenomatoid malformation, is postulated to be a disorder of pulmonary airway morphogenesis and encompasses 5 different types with distinct levels or stages of tracheobronchial development. We present a unique case of type 2 congenital pulmonary airway malformation with a previously undocumented combination of multiple extrapulmonary anomalies, featuring ipsilateral multicystic renal dysgenesis, contralateral renal agenesis, and ovarian germ cell hypoplasia, diagnosed in a 19-week gestational age fetus by autopsy. Epithelial cells comprising the pulmonary lesions were positive for thyroid transcription factor-1, surfactant protein-B, and cytokeratin-7 but negative for cytokeratin-20 immunostainings, with the pattern seen in normal terminal bronchioles. Chromosomal analysis showed a normal female karyotype, despite a high estimated risk for Down syndrome suggested by the low maternal serum α-fetoprotein level.

Amnion Rupture Sequence and Severe Congenital High Airway Obstruction

Amnion rupture sequence (ARS) is associated with amputations and often with compression and constriction deformities. Bands of amnion can also attach to the head, causing congenital torticollis. We describe the case of a premature infant with ARS and congenital airway obstruction. The infant had large, hyperechoic lungs and massive ascites diagnosed prenatally, suggestive of high airway obstruction. This case might represent a novel and causative association between ARS and congenital high-airway obstruction syndrome (CHAOS).

Selected ReportsEndotracheal Castleman Disease: A Case Report

Castleman disease (CD) is an uncommon benign lymphoid hyperplasia with several clinical and morphologic variants associated with distinct outcomes. Pulmonary CD has been reported as a rare extranodal manifestation in the literature. However, CD presenting as an obstructive mass in the airway has not been documented. We report a case of localized hyaline-vascular CD presenting as an endotracheal lesion. The patient was a 50-year-old woman with Marfan syndrome. The lesion caused near-complete airway obstruction with respiratory insufficiency. The patient underwent laser resection, and the diagnosis of CD was supported by comprehensive studies including histopathologic, immunohistochemical, and molecular methods.

Terminal respiratory unit type lung adenocarcinoma is associated with distinctive EGFR immunoreactivity and EGFR mutations.

Approximately 10% to 20% of nonsmall cell lung cancer patients respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib. Responders are mostly nonsmokers and women with tumors displaying bronchioloalveolar features. Mutations of the tyrosine kinase domain of the EGFR gene have been associated with a clinical response to gefitinib. A recent study reported that the terminal respiratory unit (TRU)-type adenocarcinoma shares the clinical profile and EGFR mutations of gefitinib responders. EGFR immunoreactivity in this context has not been reported in the literature. We performed a detailed immunohistochemical analysis of EGFR expression on 124 consecutive lung resection specimens for malignancy, to survey the EGFR immunoreactivity in lung cancers in general and to correlate EGFR immunoreactivity with EGFR mutations and TRU-type histology. EGFR positivity was seen most frequently in squamous cell carcinomas (77%), followed by TRU-type adenocarcinomas (63%), large cell carcinomas (23%), and non-TRU-type adenocarcinomas (12%). A distinctive basally oriented cytoplasmic positivity was observed exclusively in TRU-type adenocarcinomas. EGFR mutation was identified in 6 of 54 cases studied and all 6 cases were TRU-type adenocarcinomas. Five of six cases with EGFR mutation were positive for EGFR immunostain with the basal cytoplasmic localization. In conclusion, EGFR immunoreactivity with basal cytoplasmic pattern was exclusively seen in TRU-type adenocarcinoma and a subset of these cases was seen with EGFR mutations in the responders to EGFR inhibitor therapy.

Protein expression of the tumor suppressors p16INK4A and p53 and disease progression in recurrent respiratory papillomatosis

Background: Recurrent respiratory papillomatosis (RRP) is a benign condition that rarely metastasizes as invasive squamous cell carcinoma. Although this disease is associated with human papillomavirus, the role of this virus in tumorigenesis is unclear.