Article

Cathepsin-k expression in pulmonary lymphangioleiomyomatosis.

Department of Pathology, University of Verona, Verona, Italy.
Modern Pathology (Impact Factor: 6.36). 01/2009; 22(2):161-6. DOI: 10.1038/modpathol.2008.189
Source: PubMed

ABSTRACT Lymphangioleiomyomatosis is a rare and progressive lung cystic disease, caused by the infiltration of lung parenchyma by mesenchymal cells characterized by co-expression of contractile proteins and melanocytic markers. The pathogenesis of lymphangioleiomyomatosis is determined by mutations affecting tuberous sclerosis complex (TSC) genes, with eventual deregulation of the Rheb/mTOR/p70S6K pathway, and the potential therapeutic activity of mTOR inhibitors is currently under investigation. To better understand the molecular mechanisms involved in the pathogenesis of lymphangioleiomyomatosis, we investigated the expression of cathepsin-k (a papain-like cysteine protease with high matrix-degrading activity). The rationale of this choice was based on the recent demonstration that mTOR inhibitors can regulate major functional activities of osteoclasts, including the expression of cathepsin-k. The immunohistochemical study included 12 cases of lymphangioleiomyomatosis. Twelve angiomyolipomas and several lung diseases (sarcoidosis, organizing pneumonia, usual interstitial pneumonia, emphysema) were investigated as controls. In all lymphangioleiomyomatosis cases, strong cathepsin-k immunoreactivity was demonstrated, restricted to lymphangioleiomyomatosis cells. Similar expression levels were observed in renal angiomyolipomas. These observations extend the knowledge regarding the immunophenotypic profile of lymphangioleiomyomatosis cells, and provide a useful new marker for diagnosis in difficult cases (eg, in small transbronchial biopsies). The strong expression of such a potent papain-like cysteine protease in lymphangioleiomyomatosis cells can significantly contribute to the progressive remodelling of lung parenchyma observed in this deadly disease, with eventual formation of lung cysts. It is possible to speculate that mTOR inhibitors may exert part of their action by limiting the destructive remodelling of lung structure.

1 Follower
 · 
125 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: In 1963, the first bronchoscopic lung biopsy was performed. Less than 10 years later, the technique of transbronchial lung biopsy using a flexible bronchoscope was introduced into clinical practice, significantly reducing the rate of major complications and the rate of surgical lung biopsies in patients with diffuse parenchymal lung diseases. The diagnostic yield of transbronchial lung biopsy varies among various parenchymal lung diseases. In pulmonary sarcoidosis and lymphangitis carcinomatosa, a diagnosis can be obtained in up to 80% of patients. This method is considered inadequate, however, in identifying more complex histological patterns such as usual interstitial pneumonitis or nonspecific interstitial pneumonitis. Introduction of the ‘jumbo forceps’ and of a more ‘surgically oriented’ procedural setting (patients deeply sedated and intubated) allowed larger and more numerous lung specimens to be obtained without a significant increase of complications such as pneumothorax or bronchial bleeding. However, the possibility to obtain enough parenchymal tissue for a morphological diagnosis of complex patterns remained unmet. Recently, the use of cryoprobes has achieved a significant impact on this issue allowing to obtain large quantity of tissue. Recent studies document that with transbronchial cryobiopsies the diagnosis of usual interstitial pneumonitis can be made confidently by pathologists with a good inter-observer agreement. Pneumothorax is the main complication (reported in up to one fourth of cases in some series); bronchial bleeding is easily controlled using Fogarty balloon. Transbronchial cryobiopsy is a promising new technique that may become a valid alternative to surgical lung biopsy in the near feature.
    Respirology 06/2014; 19(5). DOI:10.1111/resp.12309 · 3.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: PEComas are mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells which are characterized by the coexpression of muscle and melanogenesis markers. This group of lesions includes angiomyolipoma, clear-cell “sugar” tumor of the lung and extrapulmonary sites, lymphangioleiomyomatosis, clear-cell myomelanocytic tumor of the falciform ligament/ligamentum teres and rare clear-cell tumors of other anatomical sites. In the genitourinary tract PEComas have been described in the kidney, bladder, prostate, testis and urethra. Although most PEComas behave as benign tumors, some are potentially malignant and criteria for malignancy have been suggested for both and renal and extrarenal lesions. Recently the expression of cathepsin K has been demonstrated in a large number of PEComas and has been proposed as a relatively specific marker to distinguish these proliferations from the majority of human cancers. In addition, a distinctive subset of PEComas harboring TFE3 gene fusions have been reported, giving rise to a possible relationship between them and MiTF/TFE family translocation renal cell carcinomas. The genetic alterations of tuberous sclerosis complex that promote activation of the mTOR pathway have been identified in PEComas. Therapy with mTORC1 inhibitors has been shown to be effective in some cases.
    Seminars in Diagnostic Pathology 02/2015; 32(2). DOI:10.1053/j.semdp.2015.02.006 · 1.80 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To review the available published data regarding the incidence, mechanisms of pathogenesis, clinical presentations and management of pneumonitis caused by anti-cancer treatments (radiotherapy (RT) and systemic agents) that are included in the guidelines of the treatment of breast cancer (BC) and address the issues on the current grading classification of pneumonitis. A literature search was performed between July and October 2013 using PubMed for papers published from January 1989 to October 2013. Any clinical trial, case report, case series, meta-analysis or systematic review that reported on pulmonary toxicity of any BC therapeutic modality was included (only papers published in English). Most of anticancer treatments currently used in the management of BC may induce some degree of pneumonitis that is estimated to have an incidence of 1-3 %. There is an obvious distinction between chemotherapy- and targeted treatment-related lung toxicity. Moreover, the current classification of pneumonitis needs to be modified as there is a clear diversity in grade 2. As pneumonitis is relatively common and reported as side effect of new anticancer agents, physicians need to be aware of the clinical and radiological manifestations of drug- and RT-induced toxicities in patients with BC. A key recommendation is the subdivision of grade 2 cases to two subgroups. We provide an algorithm, along with real life cases as managed in the breast Unit of Royal Marsden Hospital, with the aim to guide physicians in managing all possible eventualities that may come across in clinical practise.
    Breast Cancer Research and Treatment 06/2014; 146(2). DOI:10.1007/s10549-014-3016-5 · 4.20 Impact Factor

Full-text

Download
58 Downloads
Available from
May 30, 2014