Ets-2 is a ubiquitous transcription factor activated after phosphorylation at threonine-72. Previous studies highlighted the importance of phosphorylated ets-2 in lung inflammation and extracellular matrix remodeling, two pathways involved in pulmonary fibrosis. We hypothesized that phosphorylated ets-2 played an important role in pulmonary fibrosis, and we sought to determine the role of ets-2 in its pathogenesis. We challenged ets-2 (A72/A72) transgenic mice (harboring a mutated form of ets-2 at phosphorylation site threonine-72) and ets-2 (wild-type/wild-type [WT/WT]) control mice with sequential intraperitoneal injections of bleomycin, followed by quantitative measurements of lung fibrosis and inflammation and primary cell in vitro assays. Concentrations of phosphorylated ets-2 were detected via the single and dual immunohistochemical staining of murine lungs and lung sections from patients with idiopathic pulmonary fibrosis. Ets-2 (A72/A72) mice were protected from bleomycin-induced pulmonary fibrosis, compared with ets-2 (WT/WT) mice. This protection was characterized by decreased lung pathological abnormalities and the fibrotic gene expression of Type I collagen, Type III collagen, α–smooth muscle actin, and connective tissue growth factor. Immunohistochemical staining of lung sections from bleomycin-treated ets-2 (WT/WT) mice and from patients with idiopathic pulmonary fibrosis demonstrated increased staining of phosphorylated ets-2 that colocalized with Type I collagen expression and to fibroblastic foci. Lastly, primary lung fibroblasts from ets-2 (A72/A72) mice exhibited decreased expression of Type I collagen in response to stimulation with TGF-β, compared with fibroblasts from ets-2 (WT/WT) mice. These data indicate the importance of phosphorylated ets-2 in the pathogenesis of pulmonary fibrosis through the expression of Type I collagen and (myo)fibroblast activation.

Abstract

A 57-year-old male with a history of hypertension presented with shortness of breath, intermittent substernal chest pain, subjective fevers, and a 30-pound weight loss. He was found to have a bladder mass four months prior to presentation, for which he underwent cystoscopy and surgical removal. Pathology demonstrated high-grade superficial plasmacytoid urothelial carcinoma extending into the submucosa but not the muscularis propria. Given the superficial nature of his bladder cancer, a cystectomy was deferred. He was subsequently lost to follow-up care. On arrival, physical exam was notable for tachycardia, tachypnea, and distant heart sounds. An ECG showed an incomplete right bundle branch block and sinus tachycardia. Computed tomography pulmonary angiography revealed a three-cm pericardial effusion. Transthoracic echocardiography confirmed this finding and revealed a mass in the right ventricle (RV) extending into the outflow tract and infiltrating the free wall. The RV was dilated with an estimated RV systolic pressure of 37 mmHg. Pericardiocentesis yielded nearly one liter of serosanguinous fluid with non-diagnostic cytology. Partial median sternotomy with biopsy showed pathologic findings consistent with metastatic urothelial carcinoma, plasmacytoid variant. A PET scan showed increased uptake exclusively in the heart. The oncology team discussed options with the patient including chemotherapy and palliative care. The patient decided to withhold further therapy and went home with hospice care. He died two months later.

Discussion

Bladder cancer is the fourth most common cancer in men in the United States. Most patients (69%) with metastatic bladder cancer have multiple organs involved; conversely, our patient had a PET scan indicating his disease was localized to the heart. Plasmacytoid urothelial carcinoma is a rare subtype of bladder cancer, and is estimated to make up less than three percent of all invasive bladder carcinomas. At the time of this publication we are aware of only three other reported instances of isolated cardiac metastasis with urothelial bladder origin; none of which were the plasmacytoid variant.

Conclusion

This case highlights a previously unreported presentation of plasmacytoid urothelial carcinoma. Clinicians must remember that even superficial cancers can have significant metastatic potential.

Background

18F-FDG PET/CT is widely utilized in the management of cancer patients. The aim of this paper was to comprehensively describe the specific methodology utilized in our single-institution cumulative retrospective experience with a multimodal imaging and detection approach to 18F-FDG-directed surgery for known/suspected malignancies.

Methods

From June 2005-June 2010, 145 patients were injected with 18F-FDG in anticipation of surgical exploration, biopsy, and possible resection of known/suspected malignancy. Each patient underwent one or more of the following: (1) same-day preoperative patient diagnostic PET/CT imaging, (2) intraoperative gamma probe assessment, (3) clinical PET/CT specimen scanning of whole surgically resected specimens (WSRS), research designated tissues (RDT), and/or sectioned research designated tissues (SRDT), (4) micro PET/CT specimen scanning of WSRS, RDT, and/or SRDT, (5) total radioactivity counting of each SRDT piece by an automatic gamma well counter, and (6) same-day postoperative patient diagnostic PET/CT imaging.

Results

Same-day 18F-FDG injection dose was 15.1 (± 3.5, 4.6-26.1) mCi. Fifty-five same-day preoperative patient diagnostic PET/CT scans were performed. One hundred forty-two patients were taken to surgery. Three of the same-day preoperative patient diagnostic PET/CT scans led to the cancellation of the anticipated surgical procedure. One hundred forty-one cases utilized intraoperative gamma probe assessment. Sixty-two same-day postoperative patient diagnostic PET/CT scans were performed. WSRS, RDT, and SRDT were scanned by clinical PET/CT imaging and micro PET/CT imaging in 109 and 32 cases, 33 and 22 cases, and 49 and 26 cases, respectively. Time from 18F-FDG injection to same-day preoperative patient diagnostic PET/CT scan, intraoperative gamma probe assessment, and same-day postoperative patient diagnostic PET/CT scan were 73 (± 9, 53-114), 286 (± 93, 176-532), and 516 (± 134, 178-853) minutes, respectively. Time from 18F-FDG injection to scanning of WSRS, RDT, and SRDT by clinical PET/CT imaging and micro PET/CT imaging were 389 (± 148, 86-741) and 458 (± 97, 272-656) minutes, 619 (± 119, 253-846) and 661 (± 117, 433-835) minutes, and 674 (± 186, 299-1068) and 752 (± 127, 499-976) minutes, respectively.

Conclusions

Our multimodal imaging and detection approach to 18F-FDG-directed surgery for known/suspected malignancies is technically and logistically feasible and may allow for real-time intraoperative staging, surgical planning and execution, and determination of completeness of surgical resection.