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D.W. Henderson

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    MS10 - Beyond Lung Cancer - The Pathology of Intra-Thoracic Mimics (ID 27)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Pathology
    • Presentations: 1
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      MS10.3 - Pleural Neoplasms (ID 503)

      14:00 - 15:30  |  Author(s): D.W. Henderson

      • Abstract
      • Presentation
      • Slides

      Pleural neoplasms may be difficult to diagnose because they must be distinguished from metastatic malignancy involving the pleura, and from benign reactive processes causing pleural thickening. In contrast to primary lung neoplasms, primary pleural neo­plasms are uncommon, with secondary involvement being more frequent. A correct diagnosis is important, so that appropriate therapy can be delivered. Also, the diagnosis may affect the pateint’s prospects for compensation. The most common primary pleural neoplasm is mesothelioma, but compared to lung tumours even mesotheliomas are relatively rare. Mesotheliomas exhibit a wide variety of histologic patterns, which may be confused with other neo­plasms. Here we consider those other pleural lesions that must be differen­tiated from mesothelioma. Secondary Malignant Neoplasms Affecting the Pleura Secondary neoplasms represent the most common malignancy affecting the pleura, with lung carcinoma being the most common, followed by metastatic breast cancer, malignant lymphoma, (including Hodgkin and non-Hodgkin malignant lymphomas). Metastatic carcinomas of ovarian or gastric origin, malignant melanoma and sarcomas account for only a small percentage of cancer-associated pleural disease (about 5%). Some of these may show diffuse infiltration of the pleura in a pattern indistinguishable from pleural malignant mesothelioma macroscopically and radiologically. The majority of such so-called pseudomesotheliomatous neoplasms originate from the lung, but metastases from kidney, thyroid gland, larynx, stomach and cutaneous malignant melanoma as well as various sarcomas, including malignant phyllodes tumor, have also been described. Renal cell carcinoma (RCC) and amelanotic malignant melanoma may also metastasize to the pleura. RCCs with a sarcomatoid pattern can present a diagnostic problem. Labelling for RCC-related markers such as CD10 can also be seen in mesotheliomas and in sarcomatoid RCCs, the other RCC markers may be negative: correlation with imaging studies is imperative. Rare cases of sarcoma metastatic to the pleura may mascerade as mesothelioma and comprehensive clinical history is of highest imprtance. Other Neoplasms Arising in the Pleura Thymoma Affecting the Pleura Thymoma may spread into the pleura from an anterior mediastinal thymoma, but primary pleural thymomas are described and can present as localised masses or with diffuse pleural thickening. The concept of primary pleural thymoma has become accepted, but only about 25–30 cases have been reported to date. Spindle Cell Neoplasms Synovial sarcoma of the pleura Both biphasic and monophasic synovial sarcomas (SySa) are characterized by a distinctive t(X;18) chromosomal translocation and the production of the resultant alternative fusion genes, SYT-SSX1 or SYT-SSX2. SySa are well recognised as primary intrathoracic neoplasms in the pleura, where they can be confused with biphasic or sarcomatoid mesothelioma, carcinosarcoma /spindle cell carcinoma, or a biphasic pulmonary blastoma. Clinical features, immunohistochemistry and electron microscopsy are of limited usefulness and it is the detection of the t(X;18) chromosomal translocation and expression of the resultant SYT-SSX1 or SYT-SSX2 that is diagnostic of SySa. This can be done by FISH, but PCR is more sensitive and we consider molecular analysis of t(X;18) to be mandatory for discrimination between a genuine pleural SySa versus a biphasic or monophasic mesothelioma with histological appearances that mimic SySa. Solitary Fibrous Tumors (SFTs) Of Pleura Solitary fibrous tumors (SFTs) are uncommon localized spindle-cell fibroblastoid neoplasms. They most commonly arise in relation to the visceral pleura (~80%) or the parietal pleura, but they can occur in the mediastinum, lung parenchyma or related to pericardium or diaphragm. Terms such as submesothelial fibroma, fibrous mesothelioma and localized fibrous tumor have been used as synonyms in the past. Localized fibrous tumor might be the best term, because multiple simultaneous tumours have been described but 'SFT' is well established. Thoracic SFTs can vary greatly in size abd have a peak incidence between the 4[th] and 6[th] decade. SFTs are often incidental findings in asymptomatic patients, and the radiologic appearances may suggest the diagnosis, but a biopsy is always required. Symptoms can be related to the size and site of the tumor with compression of surrounding tissues. The histology ranges from the 'patternless pattern' of Stout to 'herringbone', cellular, myxoid and hemangiopericytic or angiofibromatoid areas. The mitotic index may be useful to predict malignant behaviour. Desmoid Tumors of the Pleura Desmoid tumors in the region of the chest wall are well recognized and can impinge upon the parietal pleura, but primary desmoid tumors of the pleura and lung are extremely rare. Benign and Malignant Nerve Sheath Tumors Neoplasms that have histologic and immunohistochemical features of nerve sheath tumors can occur as primary tumours in the pleural cavity. Benign ones typically show Verocay bodies and Antoni A and B areas. When malignant, these cells can cause major diagnostic confusion. Immunohistochemical staining with neural markers such as S100 protein is helpful to confirm a neurogenic origin. Inflammatory Myofibroblastic Tumors Inflammatory pseudotumors (plasma cell granuloma; inflammatory myofibroblastic tumor) may occasionally involve the pleura. They consist of of a proliferation of spindle cells with varying numbers of inflammatory cells, with prominene of plasma cells. Current thinking favours the concept that these are neoplastic lesions with the capacity in some cases for multicentricity, angioinvasion and metastasis (especially in older patients in whom IHC for anaplastic lymphoma kinsae (ALK) is negative). Epithelioid Hemangioendothelioma of the Pleura Epithelioid hemangioendothelioma is a malignant angioformative neoplasm, where the neoplastic endothelial cells are epithelioid and sometimes quite bland in appearance. The pattern in H&E-stained sections may be virtually indistinguishable from mesothelioma, and both may label for thrombomodulin and in some cases, cytokeratins. Labelling for endothelial markers such as CD31, CD34 or factor VIII-RAG aids in the diagnosis. Pleuropulmonary Blastoma Pleuropulmonary blastomas are rare in the pleura and mostly occur in early childhood. Tumours consist of primitive cells underneath an epithelium with a cambium layer-like appearance as seen in sarcoma botryoides. Rhabdomyoblasts may be found and anaplastic sarcomatous elements, such as embrynal rhabdomyosarcoma, fibrous sarcoma, chondrosarcoma and undifferentiated sarcoma, may be present. Pleural Lymphomas Primary pleural lymphomas are rare, with primary effusion lymphoma (PEL) and pyothorax-associated lymphoma being the most common. In our experience, most cases of pleural lymphoma represent secondary spread in cases of previously-diagnosed extrapleural lymphoma.

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    P2.14 - Poster Session 2 - Mesothelioma (ID 196)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Mesothelioma
    • Presentations: 1
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      P2.14-008 - Effect of Aquaporin 1 Modulation in Malignant Pleural Mesothelioma: Inhibition of Cell Proliferation and Colony Formation in vitro and Tumour Growth in vivo using a Heterotopic Mouse Model (ID 2615)

      09:30 - 16:30  |  Author(s): D.W. Henderson

      • Abstract

      Aquaporin 1 (AQP1) has been shown to be an independent prognostic marker for survival in malignant pleural mesothelioma (MPM). AQP1 is a trans-membrane protein normally expressed in mesothelial cells and is part of a family of proteins involved in fluid homeostasis, cell proliferation and motility. AQPs have been implicated in various aspects of tumour development. The aim of the current study was to determine the functional role of AQP1 in MPM, using in vitro and in vivo models.

      Primary MPM cells obtained from patient’s pleural effusions and the MPM cell line NCI-H226 were subjected to a specific pharmacological AQP1 blocker and AQP1 siRNA knockdown and examined for proliferation and colony formation using MTS and anchorage independent assays. Levels of AQP1 expression were determined by immunohistochemistry and RT-PCR. The influence of AQP1 on tumour growth in vivo was studied using a heterotopic mouse model. Briefly, 5 x 10[6] NCI-H226 cells were injected subcutaneously in the hind flank of BALB/C nude mice and allowed to grow to 100 mm[3] before daily intra-tumour injections of AQP1 blocker. Tumour size was measured daily.

      AQP1 expression correlates with cell proliferation in primary MPM cells (R[2] = 0.69). Blockade of AQP1 with pharmacological blocker or siRNA knockdown in MPM cells was shown to significantly decrease cell proliferation, both in NCI-H226 (p < 0.05) and primary MPM cells expressing AQP1 (p < 0.05). Primary MPM, where more than 20% of tumour cells expressed AQP1, showed greater reduction in proliferation compared to cells having AQP1 expression <20%. Application of AQP1 blocker decreased both the number and size of colonies formed after NCI-226 cells were subjected to anchorage independent growth (p < 0.05). In a pilot study using the heterotopic mouse model the size of tumours was decreased after 5 days using 20 μM of AQP1 blocker compared to an untreated control (n=6 for each group).

      Results indicate that AQP1 plays a functional role in MPM. Modulation of AQP1 decreases cell proliferation and colony formation as well as the growth of MPM tumours in a heterotopic mouse model. Larger scale animal studies are required to further understand the role of AQP1 in MPM and the potential clinical implications of an AQP1 blocker in the treatment of MPM