Sarcoidosis is an immune-mediated multisystem disease characterized by the formation of non-caseating granulomas. The pathogenesis of sarcoidosis is unclear, with proposed infectious or environmental antigens triggering an aberrant immune response in susceptible hosts. Multiple pro-inflammatory signaling pathways have been implicated in mediating macrophage activation and granuloma formation in sarcoidosis, including IFN-γ/STAT-1, IL-6/STAT-3, and NF-κB. It is difficult to distinguish sarcoidosis from other granulomatous diseases or assess disease severity and treatment response with histopathology alone. Therefore, development of improved diagnostic tools is imperative. Herein, we describe an efficient and reliable technique to classify granulomatous disease through selected gene expression and identify novel genes and cytokine pathways contributing to the pathogenesis of sarcoidosis. We quantified the expression of twenty selected mRNAs extracted from formalin-fixed paraffin embedded (FFPE) tissue (n=38) of normal lung, suture granulomas, sarcoid granulomas, and fungal granulomas. Utilizing quantitative real-time RT-PCR we analyzed the expression of several genes, including IL-6, COX-2, MCP-1, IFN-γ, T-bet, IRF-1, NOX2, IL-33, Eotaxin-1 and revealed differential regulation between suture, sarcoidosis, and fungal granulomas. This is the first study demonstrating that quantification of target gene expression in FFPE tissue biopsies is a potentially effective diagnostic and research tool in sarcoidosis.

Monoglyceride lipase (MGL) is a recently discovered cancer-related protein. The role of MGL in tumorigenesis remains to be fully elucidated. We have previously shown that MGL expression was reduced or absent in multiple human malignancies, and overexpression of MGL inhibited cancer cell growth. Here, we have generated the MGL knockout mice to further investigate the role of MGL in tumorigenesis in vivo. Our results indicate that MGL-deficient (MGL+/−, MGL−/−) mice exhibited a higher incidence of neoplasia in multiple organs, including the lung, spleen, liver and lymphoid tissues. Interestingly, lung neoplasms were the most common neoplastic changes in the MGL-deficient mice. Importantly, MGL-deficient animals developed premalignant high-grade dysplasia and adenocarcinomas in their lungs. Investigation of the MGL expression status in lung cancer specimens from patients also revealed that MGL expression was significantly reduced in the majority of primary human lung cancers when compared to corresponding matched normal tissues. Furthermore, mouse embryonic fibroblasts (MEFs) from MGL-deficient animals showed characteristics of cellular transformation including increased cell proliferation, foci formation and anchorage-independent growth. Our results also indicate that MGL deficiency was associated with activation of EGFR and ERK. In addition, pro-inflammatory molecules COX-2 and TNF-α were also activated in the MGL-deficient lung tissues. Thus, our results provide new insights into the novel role of MGL as an important negative regulator of EGFR, COX-2 and TNF-α. Accordingly, EGFR and COX-2/TNF-α activation/induction is expected to play important roles in MGL deficiency-driven lung tumors. Collectively, our results implicate the tumor suppressive role of MGL in preventing tumor development in vivo, particularly in context to the lung cancer, and highlight its role as a potential tumor suppressor.

References 1. Yener NA, Balikci A, Cubuk R, Midi A, Orki A, Eren Topkaya A. Primary lymphoepithelioma-like carcinoma of the lung: report of a rare case and review of the literature. Turk Patoloji Derg. 2012;28:286-289.

It was feasible to obtain pre- and postsurgical information from patients and surgeons. We anticipate statistically meaningful results about treatment alternatives in 3 to 5 years.

Background: Small cell lung cancer is a neuroendocrine neoplasm representing about 15 percent of all lung cancers. Sarcoidosis is a multisystem granulomatous disease. The involvement of mediastinal lymph nodes is common in both and makes the diagnosis challenging when these conditions coexist. We report a rare case of a patient with history of sarcoidosis who was diagnosed with small cell lung cancer. Case presentation: 65-year-old African American female with history of sarcoidosis, who presented with right sided shoulder pain for two months. CT thorax showed right upper lobe nodule with mediastinal and bilateral hilar lymphadenopathy. FDG-PET scan showed increased uptake in the right upper lobe and in mediastinal and hilar lymph nodes. She subsequently underwent an EBUS with biopsies of multiple lymph node stations. Pathology of these lymph nodes revealed non-necrotizing granulomas without evidence of malignancy. She underwent a CT guided biopsy of the right upper lobe lesion and pathology was consistent with small cell carcinoma. It was unclear whether the enlarged and active mediastinal and hilar lymph nodes were related to sarcoidosis or small cell cancer. A multidisciplinary meeting was conducted and decided to treat the patient presumably as small cell cancer with nodal disease. She was given 2 cycles of carboplatin and etoposide. Follow-up CT thorax after the second cycle showed decrease in size of the nodule along with mediastinal and hilar lymph nodes. She also underwent radiation therapy including mediastinum in the field of radiation. Discussion: Sarcoid-like reactions have been noted either in the vicinity of the tumor or within the regional lymph nodes draining that particular tumor. This has been described in less than 1 percent of lung cancers and mostly in squamous cell lung cancers. True sarcoidosis may be confused with a sarcoid-like reaction in cancer patients. It was not possible to definitively differentiate if the nodal involvement was from sarcoidosis or small cell cancer metastasis or a sarcoid like reaction in our patient. Given the diagnostic dilemma, we treated her nodal involvement as small cell lung cancer metastasis since under treatment could lead to relapse and compromise survival.