Diagnostic Accuracy of Endobronchial Optical Coherence Tomography for the Microscopic Diagnosis of Usual Interstitial Pneumonia.

Rationale: Early, accurate diagnosis of interstitial lung disease (ILD) informs prognosis and therapy, especially in idiopathic pulmonary fibrosis (IPF). Current diagnostic methods are imperfect. High-resolution computed tomography has limited resolution, and surgical lung biopsy (SLB) carries risks of morbidity and mortality. Endobronchial optical coherence tomography (EB-OCT) is a low-risk, bronchoscope-compatible modality that images large lung volumes in vivo with microscopic resolution, including subpleural lung, and has the potential to improve the diagnostic accuracy of bronchoscopy for ILD diagnosis. Objectives: We performed a prospective diagnostic accuracy study of EB-OCT in patients with ILD with a low-confidence diagnosis undergoing SLB. The primary endpoints were EB-OCT sensitivity/specificity for diagnosis of the histopathologic pattern of usual interstitial pneumonia (UIP) and clinical IPF. The secondary endpoint was agreement between EB-OCT and SLB for diagnosis of the ILD fibrosis pattern. Methods: EB-OCT was performed immediately before SLB. The resulting EB-OCT images and histopathology were interpreted by blinded, independent pathologists. Clinical diagnosis was obtained from the treating pulmonologists after SLB, blinded to EB-OCT. Measurements and Main Results: We enrolled 31 patients, and 4 were excluded because of inconclusive histopathology or lack of EB-OCT data. Twenty-seven patients were included in the analysis (16 men, average age: 65.0 yr): 12 were diagnosed with UIP and 15 with non-UIP ILD. Average FVC and DlCO were 75.3% (SD, 18.5) and 53.5% (SD, 16.4), respectively. Sensitivity and specificity of EB-OCT was 100% (95% confidence interval, 75.8-100.0%) and 100% (79.6-100%), respectively, for both histopathologic UIP and clinical diagnosis of IPF. There was high agreement between EB-OCT and histopathology for diagnosis of ILD fibrosis pattern (weighted κ: 0.87 [0.72-1.0]). Conclusions: EB-OCT is a safe, accurate method for microscopic ILD diagnosis, as a complement to high-resolution computed tomography and an alternative to SLB.

The effect that pathologic and radiologic interpretation of invasive and non-invasive areas in lung adenocarcinoma has on T-stage and treatment.

Lung adenocarcinoma is currently staged based on invasive tumor size, excluding areas of lepidic (in situ) growth. Invasive tumor size may be determined by pathologic assessment of a surgical specimen or radiographic assessment on computerized tomography (CT) scan. When invasive tumor size is the primary stage determinate, radiographic-pathologic discordance or discordant interpretation among pathologists may alter tumor stage and treatment. We reviewed 40 cases of non-mucinous pulmonary adenocarcinoma in which tumor size was the only stage-determinant. We determined the inter-observer variability when microscopically assessing architectural patterns and its effect on pathologic stage and treatment. Additionally, we correlated pathologic and radiographic assessment of invasive tumor size and its effect on tumor stage and treatment. The intraclass correlation among three pathologists was 0.9879; all three pathologists agreed on T-stage in 75% of cases. Four cases of pathologic disagreement had the potential to alter therapy. Intraclass correlation between the pathologists and invasive tumor size determined by CT scan was 0.8482. In 23 cases (57.5%) the pathologic T-stage differed (it increased >90% of the time) from clinical T-stage (determined by CT scan) based on invasive tumor size. Five of the radiographically-pathologically discrepant cases resulted in a stage change that had the potential to alter adjuvant therapy. Our findings suggest the stage differences in pathologic staging are prognostically relevant, but unlikely to impact routine selection of adjuvant therapy, and the observed variability in clinical stage tends to select against overuse of neoadjuvant therapy when invasive tumor size is the primary stage-determinant.

Noninvasive assessment of mitochondrial organization in three-dimensional tissues reveals changes associated with cancer development.

Mitochondrial organization is often altered to accommodate cellular bioenergetic and biosynthetic demands. Changes in metabolism are a hallmark of a number of diseases, including cancer; however, the interdependence between mitochondrial metabolic function and organization is not well understood. Here, we present a noninvasive, automated and quantitative method to assess mitochondrial organization in three-dimensional (3D) tissues using exclusively endogenous two-photon excited fluorescence (TPEF) and show that mitochondrial organization reflects alterations in metabolic activities. Specifically, we examine the organization of mitochondria within live, engineered epithelial tissue equivalents that mimic normal and precancerous human squamous epithelial tissues. We identify unique patterns of mitochondrial organization in the different tissue models we examine, and we attribute these to differences in the metabolic profiles of these tissues. We find that mitochondria are clustered in tissues with high levels of glycolysis and are more highly networked in tissues where oxidative phosphorylation is more dominant. The most highly networked organization is observed within cells with high levels of glutamine consumption. Furthermore, we demonstrate that mitochondrial organization provides complementary information to traditional morphological hallmarks of cancer development, including variations in nuclear size. Finally, we present evidence that this automated quantitative analysis of endogenous TPEF images can identify differences in the mitochondrial organization of freshly excised normal and pre-cancerous human cervical tissue specimens. Thus, this method could be a promising new modality to assess the role of mitochondrial organization in the metabolic activity of 3D tissues and could be further developed to serve as an early cancer clinical diagnostic biomarker.

Small cell neuroendocrine carcinoma of vagina: Report of a unique case with literature review.

Small cell carcinoma (SCC) of vagina is extremely rare. The association between this tumor and high-risk HPV infection is unclear. To our knowledge, HPV status has been reported in only 3 previous cases of SCC of vagina. Herein, we present a unique case of vaginal small cell carcinoma with discordant HPV testing results between vaginal and cervical samples. We also review and discuss findings from previously reported cases of small cell carcinoma of vagina.

Utility of secretagogin as a marker for the diagnosis of lung neuroendocrine carcinoma.

Small-cell lung cancers (SCLC) and large-cell neuroendocrine carcinomas (LCNEC) are two types of high-grade pulmonary neuroendocrine carcinomas (NECs). Diagnostic neuroendocrine markers commonly include synaptophysin, chromogranin A, CD56, and insulinoma-associated protein 1 (INSM1). In this study, the utility of secretagogin (SCGN) was examined in the context of pulmonary NEC diagnosis. The study included 71 pulmonary NEC cases (18 SCLCs, 13 combined-SCLCs, 23 LCNECs, and 17 combined-LCNECs). Immunohistochemical stains of SCGN, synaptophysin, chromogranin A, CD56, and INSM1 were performed on whole tumor sections. The stains were evaluated based on combined staining intensity and the proportion of positive tumor cells. At least mild staining intensity in at least 1% of the cells was considered positive. Bioinformatic studies showed specific SCGN expression in neuroendocrine cells and NECs. SCGN showed diffuse nuclear and cytoplasmic staining in NECs with intra-tumoral heterogeneity. The non-neuroendocrine components were negative. The sensitivity of SCGN was no better than the other established neuroendocrine markers based on all NECs combined or LCNECs/c-LCNECs only. However, the sensitivity of SCGN (71%) was higher than chromogranin A (68%) for SCLCs/c-SCLCs only. The average proportion of SCGN positive tumor cells was 8% higher than chromogranin A (22% versus 14%, P = 0.0332) in all NECs and 18% higher for SCLC and c-SCLC cases only (32% versus 13%, P = 0.0054). The above data showed that SCGN could be used as a supplemental neuroendocrine marker to diagnose SCLC.

Perineural invasion of cutaneous squamous cell carcinoma and basal cell carcinoma: raising awareness and optimizing management.

BACKGROUND: Perineural invasion (PNI) by cutaneous squamous cell carcinoma (CSCC) and basal cell carcinoma (BCC) is an infrequent but not rare complication of traditionally low-morbidity skin cancers that can lead to catastrophic sequelae; 2.5% to 14% of CSCC and approximately 3% of BCC exhibit PNI. Tumors with PNI tend to be larger, have greater subclinical extension, have a higher rate of recurrence, and have a greater risk of metastases. Tumors with PNI may result in major neurologic deficits. OBJECTIVE: To review current recommendations for the management of PNI and to evaluate a treatment strategy involving excision using Mohs micrographic surgery (MMS) followed by adjunctive radiotherapy. MATERIALS AND METHODS: Cases of PNI treated with MMS and radiotherapy were reviewed for recurrence, disease-free follow-up, and adverse events. RESULTS: Twelve patients with incidental PNI treated with MMS and adjunctive radiotherapy are presented. After 3 to 32 months of follow-up, there had been no recurrences. Adverse events from radiotherapy were minor and self-limited. CONCLUSIONS: The use of adjunctive radiotherapy in these patients remains controversial. When managing superficial skin tumors with PNI, a multidisciplinary team including a cutaneous surgeon and a radiation oncologist familiar with PNI is recommended.

Histologic, immunohistochemical, microbiological, molecular biological and ultrastructural characterization of pulmonary tularemia.

Tularemia is a rare zoonotic disease caused by Francisella tularensis, a Gram-negative bacteria. The clinical manifestations of pulmonary tularemia resemble those of other airways infections. Recently, a case of pulmonary tularemia was diagnosed at Tufts Medical Center. The purpose of the current report is to document the utility of applying several diagnostic tools, including immunohistochemistry, electron microscopy, microbiology and molecular biology in confirming the diagnosis of pulmonary tularemia, particularly in convalescing cases (up to 3 weeks postpresentation) and after antibiotic therapy. Our study demonstrates the usefulness of microbiological studies followed by morphological evaluation and the limitation of the molecular biology analysis of posttherapy samples.