Metastatic breast cancer is a complex multi-step process involving the expansion of cancerous cells from the breast to other areas of the body. It is a serious complication of breast cancer, as metastatic disease in breast cancer is often fatal, with treatments mainly limited to palliation.
Breast cancer primarily metastasizes to the bone, lungs, regional lymph nodes, liver and to the brain, with the most common site being the bone. The typical environmental barriers in any metastatic event would include physical (basement membrane), chemical (Reactive oxygen species (ROS), hypoxia and low PH) and biological (immune surveillance, inhibitory cytokines and regulatory Extracellular Matrix (ECM) peptides) components. Organ-specific anatomic considerations can also influence metastasis; these include blood flow patterns from the primary tumor and the homing ability of cancer cells for certain tissues. The targeting by cancer cells of specific organs is likely regulated by chemoattractant factors and adhesion molecules, which are produced by the target organ along with the cell-surface receptors expressed by the tumor cells.
The main steps involved in the metastatic cascade of a cancer cell are:
* The cell division and growth within the primary tumor.
* Invasion of the primary tumor border (basement membrane, referred to as BM) and the local tissue surrounding the tumor by the cell.
* Intravasation of the circulatory system: the cell enters the bloodstream or lymph channels.
* The cell must survive the transit into the new environment until it ultimately arrests in the microvasculature of the secondary site.
* Extravasation to a distant site : The cell then invades into the BM of the target tissue.
* Proliferation of the cancer cell at the metastatic site.
* Formation of a micrometastasis inside the secondary site.
* Progressive colonization to form a life threatening metastasis.
The potential of a tumor cell to metastasize depends on its microenvironment, or the “niche” interactions with the local factors that promote tumor-cell growth, survival, angiogenesis, invasion and metastasis. This is explained by the theory called the "seed and soil hypothesis".
Symptoms
The symptoms produced by metastatic breast cancer vary by the location of the metastases. For instance:
* Metastatic disease to the bone causes severe, progressive pain, and, less commonly, pathological fracture, erythema over the affected bone, and swelling.
* Metastatic breast cancer to the brain causes the following symptoms: persistent, progressively worsening headache, visual changes, seizures, nausea or vomiting, vertigo, behavioral and personality changes, and increased intracranial pressure.
* Metastatic disease to the liver causes jaundice, elevated liver enzymes, abdominal pain, loss of appetite, nausea, and vomiting
* Metastatic breast cancer to the lung or pleura causes chronic cough, dyspnea, abnormal chest X-ray, and chest pain.
* Other nonspecific systemic symptoms of metastatic breast cancer include fatigue, malaise, weight loss, and poor appetite.
Seed and soil hypothesis
The seed and soil hypothesis states that specific organs harbor metastases from one type of cancer by stimulating their growth better than other types of cancer. This interaction is dynamic and reciprocal, since cancer cells modify the environment they encounter.
Extracellular matrix degradation in cancer
Cell-cell and cell-ECM matrix adhesion, motility, and localised proteolysis are mediated mainly by matrix metalloproteases (MMPs). Degradation of extracellular matrix is the starting process that facilitates metastasis. The cell develops structures called invadopodia, which are highly concentrated in several proteases and have a highly dynamic actin cytoskeleton.
Mechanisms of metalloprotease action in cell motility involve:
* Proteolytic cleavage of growth factors so that they are readily available to cells not in direct physical contact.
* Degradation of the ECM is facilitated by MMPs so that the cells can move across tissues into nearby stroma [disambiguation needed].
* Regulated receptor [disambiguation needed] cleavage to modulate migratory signaling.
Most of these processes require a delicate balance between the functions of matrix metalloproteases (MMPs) or metalloprotease-disintegrins (ADAMs) and natural tissue inhibitors of metalloproteases (TIMPs). Regulated proteolysis is an important mechanism to maintain homeostasis. There is increased expression of protease systems in cancer cells to equip them with the tools necessary to degrade the extracellular matrix and release several growth factors or transmembrane receptors. MMP-2 is upregulated in the bone, increased levels of MMP-1 and MMP-19 are observed in the brain. This in turn, upregulates the signaling pathways necessary to provide increased cell adhesion, cell motility, cell migration, invasion, cancer cell proliferation and survival.
Bone
Metastasis is the cause of about 90% of deaths due to breast cancer and roughly 70% of all patients dying of breast cancer have evidence of metastatic bone disease. The important extracellular matrix components and cell surface receptors which could help in metastasis are discussed here.
Integrin signalling
Integrin αvβ3, a cell surface adhesion molecule is important for tumor attachment, cell-cell communication between the breast tumor cells and the environment in the bone, osteoclast bone resorption, and angiogenesis. Integrin-mediated adhesion between cancer cells and osteoclasts in bone metastases induces phosphorylation of extracellular signal-regulated kinases (ERK1/2) in osteoclasts, which in turn induces osteoclast differentiation and survival..
Cancer cell-blood platelet interaction
Metastatic breast cancer cells excrete lysophosphatidic acid (LPA) that binds to receptors on tumor cells, inducing cell proliferation and release of cytokines(IL-6 and IL-8, potent bone resorptive agents) and stimulating bone resorption.
After the breast cancer cells have traveled away from the primary tumor, they establish a tight interaction with the bone microenvironment and secrete osteolytic factors capable of osteoclast formation and bone resorption. Apart from the breast tumor cells, the resident stromal cells also contribute to tumor survival. Growth factors like epidermal growth factor (EGF), fibroblast growth factor (FGF), and transforming growth factor beta (TGF-β) are implicated in the development and progression of metastatic breast cancer.
Matrix metalloproteinases (MMPs)
MMP-2 is the main metalloprotease secreted by breast cancer cells or induced in the adjacent bone stroma [disambiguation needed]; it plays an important role in the degradation of extracellular matrix essential for cancer metastasis. Tumor cells use MMP-2 secreted by bone marrow fibroblasts (BMFs). MMP-2 is stored in an inactive conformation in association with the cell surface or extracellular matrix of BMFs.. Inactive MMP-2 present on the surface of BMFs is displaced by breast cancer cells. Cancer cells can then use the proteinase to facilitate tissue invasion, which requires the degradation of connective tissue associated with vascular basement membranes and interstitial connective tissue.
Brain
Brain metastasis is observed in 10% of breast cancer patients with metastatic properties. Many of the breast cancer therapies (like targeted antibodies) fail to penetrate the blood-brain barrier (BBB), hence allowing for tumor recurrence in the Central Nervous System. Brain is a special organ for metastasis as the breast tumor cells have to pass the BBB in order to form micrometastases in the brain.
CD44
CD44, a cell-surface transmembrane glycoprotein is a receptor for hyaluronic acid involved in cell adhesion by binding to specific extracellular matrix components. A proposed mechanism for the function of CD44 may be to regulate the adhesion of circulating cancer cells in the brain to endothelium at the secondary site with the help of hyaluronate matrix ligand or by its cytoplasmic attachments to actin-associated proteins of the merlin/ezrin/radixin/moesin family .
Sialyl transferase (glycosylation modifications of gangliosides)
Cell-surface sialylation has been implicated in cell–cell interactions and overexpression of a brain sialyltransferase in breast cancer cells is a mechanism that highlights the role of cellsurface glycosylation in organ-specific metastatic interactions. Breast cancer metastasis to the brain involves mediators of extravasation through non-fenestrated capillaries, complemented by specific enhancers of blood–brain barrier crossing and brain colonization .
ECM components in breast cancer metastasis
ECM-tumor cell interactions play a critical role in each of the events of the metastatic cascade. Interactions of the breast cancer cells with integrins, fibronectin, laminins, collagens, hyaluronan, proteoglycans which can contribute to the metastatic process. Some of these proteins are discussed here in relevance to breast cancer metastasis.
Fibrinogen - Integrin
Fibronectin is an extracellular glycoprotein that can bind to integrins and other ECM components like collagen, fibrin and Heparan Sulphate ProteoGlycans(HSPGs). Several different integrins bind to fibronectin. Fibronectin-integrin interactions are important in tumor cell migration, invasion, and metastasis and also cell proliferation by signaling through integrins. Integrin-mediated tumor cell adhesion to ECM proteins can trigger signal transduction and cause upregulation of gene expression, increased tyrosine phosphorylytion of the focal adhesion kinase , activation and nuclear translocation of mitogen-activated protein (MAP) kinases.
Heparanase
Heparanase cleaves heparin sulfate chains of HSPGs which have an extensive network with several proteins on cell surface and ECM. The basic HSPG structure consists of a protein core to which several linear heparin sulfate (HS) chains are covalently O-linked and acts as an assembly of different ECM proteins, including fibronectin, laminins, and interstitial collagens, heparin-binding growth factors, chemokines, lipoproteins.
HSPGs are prominent components of blood vessels.. Binding to HS stabilizes FGFs and Vascular Endothelial Growth Factors (VEGFs) and prevents them from inactivation. HS chains function as low affinity co-receptors that promote dimerization of FGFs, hence helps in the sequestration of the GFs and causes activation of the signaling tyrosine kinase receptors even under low circulating concentrations of the growth factors. Heparanase expressed by cancer cells participates in angiogenesis and neovascularization by degrading the polysaccharide scaffold of the endothelial BM, thereby releasing angiogenic growth factors from ECM.
Tenascin
The ECM protein tenascin C (TNC) is up-regulated in metastatic breast cancer. TNC is an adhesion-modulating extracellular matrix glycoprotein. It is highly expressed in tumor stroma [disambiguation needed] and stimulates tumor cell proliferation. It is hypothsised that TNC stimulates invasion via up-regulation of MMP-1 expression through activation of MAPK pathway. MMP-1 (interstitial collagenase) cleaves collagen type I, II, III, VII and X. Hence, tenascin Coverexpression can significantly alter the collagen in the ECM and influence tumor cell migration in cartilaginous tissues.
Endoglin
Endoglin is a cell-surface disulfide-linked homodimeric glycoprotein which binds to the integrins and other RGD ligands and a coreceptor for TGF-beta. Brain metastatic breast tumor cells express endoglin in large amounts. Endoglin-overexpressing cells develop large numbers of invadopodia and endoglin is localized in these structures. Endoglin-expression in tumor cells contributes to metastasis by upregulating MMP-1 and MMP-19. MMP-19 cleaves components of the basal lamina, such as collagen type IV, laminin 5, nidogen (entactin) and other ECM proteins like tenascin, aggrecan, fibronectin. Hence endoglin-overexpression alters the proteolytic balance of the cells to higher matrix degradation and increased invasive properties of the breast cancer.
Therapies
Metastasis is a complex and interconnected multi-step process. Each step in the process is a potential target for therapies to prevent or reduce metastasis. Those steps which have a good clinical window period are the best targets for therapy. Each event in metastasis is highly regulated and requires a synergistic activation of different ECM proteins, growth factors, etc. Although the occasional patient with metastatic breast cancer benefits from surgical resection of an isolated metastasis, and most patients receive radiotherapy (often for palliation alone), during the course of their disease, the treatment of metastatic breast carcinoma typically has to involve the use of systemic therapy.
Chemotherapy
Chemotherapy is one of the most important parts of therapy for metastatic breast cancer. The Taxenes are very active in metastatic breast cancer, and abraxane, a form of paclitaxel without solvents, is approved for patients with metastatic breast cancer who either relapsed within 6 months of adjuvant chemotherapy or failed to respond to combination chemotherapy, with a higher response rate then solvent-based paclitaxel (15% vs 8%) also, abraxane can deliver a 49% higher dose of medication than solvent based paclitaxel. However, side effects are severe. Also, severe sensory neuropathy can occur in patients treated with abraxane. Combination chemotherapy is often used in patients with metastatic breast cancer, but so far, while some studies have shown that a combination of doxorubicin and paclitaxel improves response rates in metastatic breast cancer over either agent alone, there is no evidence this approach improves overall survival. Xeloda is a new chemotheraputic agent that is approved for colorectal carcinoma and metastatic breast cancer in combination with docetaxel, improved response rates from 22% to 32% when compared to docetaxel alone and overall survival from 11 months to 14 months, a fairly significant benefit. The overall response rate to doxorubicin is 40-50%, which is somewhat lower than the response rate to docetaxel, which has an overall response rate of up to 68%. Also, while doxorubicin is cardiotoxic and is contraindicated in patients with preexisting cardiac disease, docetaxel can be used in those with heart disease, and has slightly less intestinal side effects (mainly a reduction in the incidence of diarrhea. Gemzar is a new antimicrotubule that has been proven to be superior to paclitaxel alone, with an overall response rate of 40% when used in combination with paclitaxel, an 89% improvement in overall response rate when compared with paclitaxel alone (which has a 22% response rate). There was also improved overall survival and time to progression. Vinorelbine is also active in metastatic breast cancer, with an overall response rate of up to 40%. It can also be used following unsuccessful treatment with a taxene or anthracycline, when used in this setting response rates are 15-30%.
Eribulin was approved by FDA in Nov 2010.
Tamoxifen and other anti-estrogens
For estrogen-receptor positive metastatic breast carcinoma, the first line of therapy is often Tamoxifen or another anti-estrogen drug, unless there are liver metastases, significant lung invovlvement, rapidly progressive disease, or severe symptoms requiring immediate palliation. Hormonal therapy should also be used following relapse of an estrogen receptor positive breast carcinoma, because the benefit of further hormonal manipulation in such patients can be as high as 50%.
Radiotherapy
Radiotherapy is used in the treatment of metastatic breast cancer. The most common reasons for a patient with metastatic breast carcinoma to be treated with radiotherapy are:
* Spinal cord compression. Spinal cord compression is an oncological emergency, as untreated spinal cord compression can causes permanent paralysis or even death. In breast cancer, spinal cord compression occurs when either a bone metastasis or spinal metastasis began to push on the spinal cord, resulting in inflammation, and if untreated, spinal cord injury. Radiotherapy is an important part of therapy for cord compression secondary to metastatic breast cancer, along with corticosteroids and laminectomy.
* Liver metastases. Typically, pain from liver metastases responds to chemotherapy and pain medication. However, in cases when chemotherapy is contraindicated, or the liver metastases are refractory to chemotherapy, and pain medication fails to provide appropriate palliation of liver metastasis related pain, radiotherapy should be considered, as it can be effective in reliving pain and may shrink the metastases, and perhaps even extend survival in a subset of patients who have a good response to radiotherapy.
* Brain metastases. Brain metastases occur in up to 10–15% of breast cancer patients, and often, but not always, occur late in the disease. They require urgent treatment, as brain metastases can progress rapidly, and can suddenly produce life-threatening complications such as increased intracranial pressure, herniation of the brain, and seizures. Radiotherapy is essential in the treatment of brain metastases from breast cancer, as it halts tumor progression quickly and can induce a response in the majority of patients. However, in one small retrospective study of 36 patients with breast cancer metastatic to the brain, despite a high initial response rate of 82%, the duration of the response was very short, with intracranial relapse occurring on average 5.0 months after the end of therapy, and median survival being just 7.9 months. However, it did initially palliate symptoms of the brain metastases, a major objective in terminally ill patients with breast cancer.
* Bone metastases. The bones are a very common site of metastatic disease from breast cancer, and bone metastases can cause severe pain, hypercalicemia, and pathologic fracture. Radiotherapy to areas of painful bone metastases has a symptomatic response rate of more than 75% (however, a symptomatic response only means an improvement in symptoms, not a documented regression of the cancer). Radiotherapy is also indicated to prevent pathologic fracture, as well as part of postoperative treatment following repair of a pathologic fracture. Strontium 89, a radiopharmaceutical that is injected into the bloodstream, is under investigation for the treatment of bone metastases from breast cancer. Currently, there is evidence that it can relieve pain for up to three months after its administration. It is not known whether or not it can prevent pathologic fracture, but it should be considered in patients who have three or more sites of painful bone metastases who cannot be treated with external beam radiotherapy. In some patients with estrogen receptor positive breast carcinoma metastatic to the bone only, external beam radiotherapy followed by tamoxifen or another anti-estrogen may be sufficient to control disease for at least a period of time. In most cases, however, the combination of radiotherapy and hormonal therapy is not enough to maintain disease control, and chemotherapy is needed.
Alternative therapies
Some patients with metastatic breast cancer opt to try alternative therapies, such as vitamin therapy, homeopathic treatments, macrobiotic diet, chiropractic, or acupuncture. There is no evidence that any of these therapies are effective, and they may be harmful, either because patients pass up effective conventional therapies such as chemotherapy or anti-estrogen therapy in favor of alternative treatments, or because the treatments themselves are harmful, as in the case of apricot pit therapy, which exposes the patient to cyanide, or in chiropractic, which can be dangerous to patients with cancer metastatic to the spinal bones or spinal cord. Also, the macrobiotic diet is neither effective nor safe, as it could hypothetically encourage weight loss, owing to the severe dietary restrictions. There is limited evidence acupuncture could relive pain in cancer patients, but data so far is not sufficient to recommend its use outside of clinical trials. Also, there could be a risk of HIV,or hepatitis if needles are not sterilized. Currently, most oncologists discourage alternative breast cancer therapy, because there is no evidence it is effective, it may in some cases be harmful, and it often causes patients to resist the conventional therapies.
Experimental therapies
Treatment of metastatic breast cancer is currently an active area of research. A very promising experimental therapy for breast cancer is Nexavar, a drug already approved for patients with metastatic renal cell carcinoma and hepatocellular carcinoma. In a study of more than 200 patients, those who received Nexavar and the chemotheraputic agent Xeloda had longer time to progression than those who took Xeloda alone, the study said--with the median progression free survival time being 6.4 months in the Xeloda-and-Nexavar group compared to 4.1 months in the Xeloda-alone group.
Nanotherapies using nanoprobes
Recently, nanomedicine has become popular and there are several interesting developments involving the targeting of cancer cells using nanoprobes. Here are a few instances where nanoprobes are used to target specific tumor cells (based on the organ to which they have metastasized):
* Chlorotoxin, a chemical derived from the giant Israeli scorpion, binds to MMP-2 to cause endocytosis of the metalloprotease, thus reducing its activity. Chemically bonded iron oxide nanoparticles were coated with about 20 molecules of chlorotoxin and targeted to the brain metastatic cancer cells. It was found that nanoprobes reduced the brain metastatic tumors in mice by 98%.
* Nanotherapy using antibodies to herceptin coated on gold nanoparticles has showed results of slowing down the growth and invasion of aggressive breast tumors in mice. Such therapies targeted to specific cell types might be useful in the future to develop better treatments to prevent or treat metastasis in breast cancer.
Central nervous system metastases
Clinically symptomatic CNS metastases are reported to occur in 10-15% of patients with metastatic breast cancer, but in large autopsy studies, up to 40% of woman who died of metastatic breast cancer were reported to have at least one brain metastasis. CNS metastases are often viewed by patients and doctors alike as a late complication of metastatic breast cancer for which few effective treatments exist. In most cases, CNS involvement occurs after metastatic dissemination to the bones, liver, and/or lungs has already occurred, and for that reason, many patients already have refractory, terminal breast cancer by the time they are diagnosed with brain metastases. Diagnosis of brain metastases from breast cancer relies mainly on patient reported symptoms and neuroimaging.
Symptoms of brain metastases from breast cancer are:
* new onset headache
* alterations in mental status, cognition, and behavior.
* ataxia
* cranial neuropathy, which can cause diplopia, and bells palsy
* vomiting and nausea
* deficits in sensation, motor function, and speech
Breast cancer involving the CNS is traditionally viewed as a late complication of progressive metastatic disease, for which few effective treatment options exist. For all brain metastatic patients, those with controlled extra-cranial tumor, age less than 65 years, and a favorable general performance (Karnofsky performance status ≥70) fare best whereas older patients with a Karnofsky performance status <70 do poorly. However, effective treatments for brain metastases from breast cancer do exist, although symptomatic therapy alone may be chosen for those with poor performance status. Corticosteroids are crucial in the treatment of brain metastases from any origin-including the breast, and are effective in reducing peri-tumoral edema and providing symptomatic relieve.
Chemotherapy has not been found to be effective in the treatment of brain metastases from breast cancer, due to the inability of most chemotheraputic agents to penetrate the blood brain barrier. Whole brain radiation can provide a median survival of 4 to 5 months, which can be further extended by stereotactic radiosurgery months. Several nonrandomized studies have suggested that stereotactic radiosurgery may provide nearly equivalent outcomes compared to surgery followed by whole brain irradiation. Surgery tends to reduce symptoms quickly and prolong life significantly, with persistent increases in quality of life. Multiple metastases (up to three) can be removed surgically with a risk similar to that of a single lesion, providing similar benefits. At present, adjuvant radiotherapy follows surgical resection because this combined approach has been shown in general to prolong median survival significantly, to 12 months depending on the factors noted above. There is also a growing body of evidence that surgery may be useful in select patients with recurrent brain metastases. Mean survival from diagnosis of a brain metastasis varies between studies but ranges from 2 to 16 months, depending on involvement of the CNS, the extent of the extra-cranial metastatic disease, and the treatment applied. The mean 1-year survival is estimated at 20%. Improvements in the treatment of brain metastases are clearly needed.
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Multicentric study on malignant pleural mesothelioma and non-occupational exposure to asbestosC Magnani, A Agudo, CA González, A Andrion, A Calleja, E Chellini, P Dalmasso, A Escolar, S Hernandez, C Ivaldi, D Mirabelli, J Ramirez, D Turuguet, M Usel and B Terracini
Cancer Epidemiology Unit, S Giovanni B Hospital and Regional Centre for Cancer Epidemiology and Prevention, Torino, Italy; Department of Epidemiology and Cancer Registration, Catalan Institute of Oncology (ICO), Av. Gran Via s/n, Km 2.7, E-08907, L’Hospitalet de Llobregat, Spain; Department of Pathology, Ospedale Martini, Torino, Italy; entre de Seguretat i Condicions de Salut en el Treball (CSCST), Barcelona, Spain; Epidemiology Unit, Center for Study and Prevention of Cancer Firenze (CSPO), AO Careggi, Firenze, Italy; Department of Preventive Medicine and Public Health, Hospital Universitario Puerta del Mar, Cádiz, Spain; Agency for Environmental Protection (ARPA) Piemonte, Torino, Italy; Department of Pathology, Hospital Clinic, Barcelona, Spain; Former Documentation Services, Instituto Nacional de Seguridad e Higiene en el Trabajo, and Centro de Investigación y Desarrollo de Barcelona (CSIC), Barcelona, Spain; Geneva Medical Inspectorate of Factories (OCIRT) and Geneva Cancer Registry, Geneva, Switzerland
Summary Insufficient evidence exists on the risk of pleural mesothelioma from non-occupational exposure to asbestos. A population-based case–control study was carried out in six areas from Italy, Spain and Switzerland. Information was collected for 215 new histologically confirmed cases and 448 controls. A panel of industrial hygienists assessed asbestos exposure separately for occupational, domestic and environmental sources. Classification of domestic and environmental exposure was based on a complete residential history, presence and use of asbestos at home, asbestos industrial activities in the surrounding area, and their distance from the dwelling. In 53 cases and 232 controls without evidence of occupational exposure to asbestos, moderate or high probability of domestic exposure was associated with an increased risk adjusted by age and sex: odds ratio (OR) 4.81, 95% confidence interval (CI) 1.8–13.1. This corresponds to three situations:
cleaning asbestos-contaminated clothes, handling asbestos material and presence of asbestos material susceptible to damage. The estimated OR for high probability of environmental exposure (living within 2000 m of asbestos mines, asbestos cement plants, asbestos textiles, shipyards, or brakes factories) was 11.5 (95% CI 3.5–38.2). Living between 2000 and 5000 m from asbestos industries or within 500 m of industries using asbestos could also be associated with an increased risk. A dose–response pattern appeared with intensity of both sources of exposure. It is suggested that low-dose exposure to asbestos at home or in the general environment carries a measurable risk of malignant pleural mesothelioma. © 2000 Cancer Research Campaign
Keywords: asbestos; environmental exposure; mesothelioma; case–control studies
There is convincing evidence that pleural malignant mesothelioma is associated with occupational exposure to all commercial forms of asbestos (Landrigan, 1998; WHO, 1998). Although most cases of mesothelioma show a definite history of asbestos exposure at work, in population studies there is a proportion of cases that do not report any occupational exposure throughout their working life. Therefore, attention has turned to the potential risk associated with exposure at the lower doses in the general environment (Landrigan 1998).
Two circumstances for possible non-occupational exposure to asbestos have been investigated: domestic and environmental exposure. The former results from asbestos fibres brought home by workers exposed in the workplace (Gardner and Saracci, 1989). Environmental exposure may result from residence in the vicinity of asbestos mines, mills, or factories using asbestos. In many studies there is a single well-identified source of asbestos pollution termed a ‘neighbourhood exposure’. Another kind is due to residence in areas where the soil is naturally rich in asbestos or similar fibres. Both sets of circumstances have led to localized outbreaks of pleural mesotheliomas, large enough to be first recognized in the absence of formal epidemiological studies (Gardner and Saracci, 1989). The latter are needed, however, to investigate whether the industrial use of asbestos may produce sufficient environmental pollution to cause asbestos-related disease. Rarely, mesotheliomas may occur in recognizable geographical or temporal clusters when the exposure is relatively high, but they will go unnoticed when exposure is low. Although asbestos is widely found in the environment, insufficient evidence exists on the risk of mesothelioma as a consequence of general environmental exposure (Siemiatycki and Boffeta, 1998). The extent to which the general population is exposed and the potential effects of such low-dose exposure are a matter of controversy.
A multicentric population-based case–control study was therefore carried out with the main aim of measuring risk associated with low-intensity, non-occupational exposure to asbestos.
A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomesMichele Carbone, Salih Emri, A. Umran Dogan, Ian Steele, Murat Tuncer, Harvey I. Pass and Y. Izzettin Baris
Abstract | In Cappadocia, Turkey, an unprecedented mesothelioma epidemic causes 50% of all deaths in three small villages. Initially linked solely to the exposure to a fibrous mineral, erionite, recent studies by scientists from Turkey and the United States have shown that erionite causes mesothelioma mostly in families that are genetically predisposed to mineral fibre carcinogenesis. This manuscript reports, through the eyes of one of the researchers, the resulting scientific advances that have come from these studies and the social improvements that were brought about by both the scientists and members of the Turkish Government.
Mesothelioma is a cancer arising from the mesothelial cells that line the pleural, pericardial and peritoneal surfaces1,2. Although there are rare benign variants of mesothelioma, such as multicystic mesothelioma or mesothelioma of the atrioventricular node, which are not related to asbestos exposure1,2, this article focuses on the relatively more common malignant mesothelioma. In the United States there are approximately 2,500 cases and deaths per year of malignant mesothelioma, which is often related to asbestos exposure (BOX 1). Median survival is approximately 1 year from diagnosis because current therapies have only marginal effects in altering the natural course of the disease1. Although the link between asbestos exposure and mesothelioma was established in 1960, it is still unclear whether all types of asbestos cause mesothelioma
Soluble Mesothelin-Related Peptide Level Elevation in Mesothelioma Serum and Pleural EffusionsHarvey I. Pass, MD, Anil Wali, PhD, Naimei Tang, PhD, Alla Ivanova, PhD, Sergey Ivanov, PhD, Michael Harbut, MD, Michele Carbone, MD, PhD, and Jeffrey Allard, PhD
Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-related tumor which is increasing in incidence and causes an estimated 15,000 to 20,000 deaths per annum worldwide. Malignant pleural mesothelioma has a median survival of seven to ten months and a clinical pattern that usually involves substantial pain and dyspnea. It presents at a clinically advanced stage in most patients so there is a need for new methods of early detection. The fact that asbestos is the main etiologic agent for MPM means that at-risk populations can be readily identified and studied, and these populations represent ideal cohorts in which to undertake early cancer detection studies.
There have been a number of studies attempting to define biomarkers that could predate symptoms in a “high risk for MPM” population and also distinguish MPM from other malignancies. Unfortunately, the majority of these studies have had very few patients of various stages of MPM and the markers have not been prospectively evaluated. Some of these biomarkers include tissue polypeptide antigen, carcinoembryonic antigen, hyaluronic acid, and ferritin [1] as well as hyaluronic acid levels [2]. Other markers such as cytokeratins [3] and cancer antigen 125 (CA-125) [4] have been evaluated in MPM but have been inconclusive. One must conclude, therefore, that until recent reports of soluble mesothelin-related protein (SMRP) [5] and osteopontin [6] in MPM, there have been no reliable, validated serum or pleural effusion markers that can distinguish a highrisk, asbestos-exposed population without MPM from patients with established MPM, or to distinguish other malignancies from MPM.
There have been a number of studies attempting to define biomarkers that could predate symptoms in a “high risk for MPM” population and also distinguish MPM from other malignancies. Unfortunately, the majority of these studies have had very few patients of various stages of MPM and the markers have not been prospectively evaluated. Some of these biomarkers include tissue polypeptide antigen, carcinoembryonic antigen, hyaluronic acid, and ferritin [1] as well as hyaluronic acid levels [2]. Other markers such as cytokeratins [3] and cancer antigen 125 (CA-125) [4] have been evaluated in MPM but have been inconclusive. One must conclude, therefore, that until recent reports of soluble mesothelin-related protein (SMRP) [5] and osteopontin [6] in MPM, there have been no reliable, validated serum or pleural effusion markers that can distinguish a highrisk, asbestos-exposed population without MPM from patients with established MPM, or to distinguish other malignancies from MPM.
¶ Case report Malignant mesothelioma of the tunica vaginalis: a case with an unusually indolent course following radical orchidectomy and radiotherapy
Case ReportMalignant mesothelioma of the tunica vaginalis: a case with an unusually indolent course following radical orchidectomy and radiotherapy
1J L HARMSE, 1A T EVANS and 2P M WINDSOR
Directorates of 1Pathology and 2Radiotherapy and Oncology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
Abstract. Malignant mesothelioma (malignant adenomatoid tumour) of the tunica vaginalis testis is a very rare neoplasm with highly aggressive biological behaviour. Treatment is di¤cult, and widespread local invasion and/or metastatic disease at presentation are associated with a poor prognosis. In this case report we describe for the first time a patient who, despite presenting with locally advanced disease, remains well 10 years after diagnosis and treatment with radical orchidectomy and high dose radiotherapy.Case report
A 70-year-old man presented in November 1988 with a right scrotal mass. A right hydrocele had been repaired 18 years earlier, but otherwise there was no significant medical or surgical history. On examination, three cysts were palpable above the right testicle, but the organ itself was hard and craggy, which suggested the possibility of a tumour. In view of this, a radical orchidectomy was performed as the primary procedure.
The orchidectomy was performed through an inguinal incision. When the testicle was examined, the lower pole was found to be adherent to the over-lying dartos muscle and skin. A disc of skin and muscle tissue was excised in continuity with the testicle and the specimen was submitted for histo-pathological examination.
Pathological Findings
Macroscopic
The specimen comprised the right testis together with coverings and attached spermatic cord. On section a tumorous mass was seen arising from the tunica vaginalis, and consisting of dense white tissue. An adherent disc of skin and dartos muscle was included and this appeared to be widely infiltrated by pale tumour.
Microscopic
Sections from the tumour showed tubular and glandular structures set in a fibrous stroma. The gland spaces were lined by cuboidal epithelial cells displaying cytological features of malignancy and a brisk mitotic rate (Figure 1a). The tumour
invaded the testicular parenchyma and overlying muscle and skin (Figure 1b). In places, perineural invasion was a conspicuous feature (Figure 1c).
The results of previous histochemistry, immuno-histochemistry and electron microscopy examinations, performed in 1988, gave support to a diagnosis of a malignant mesothelioma, and an expert opinion also agreed with this conclusion.
Reviewoftheoriginalhistologyandrecentimmuno-histochemistry with currently available markers confirm the original diagnosis of primary malignant mesothelioma arising in the tunica vaginalis.
Multicystic Mesothelioma of the PeritoneumLiem T. Bui-Mansfield1, Gina Kim-Ahn2, Larry K. O’Bryant3
During a pelvic examination, a 44-year-old woman was found to have an abdominal mass. Pelvic sonography revealed a complex multiseptate cystic mass (Fig. 1A). MR imaging showed a 15x9x7 cm mass arising from the uterine fundus; on T2-weighted images, the mass exhibited intermediate and high signal intensity. Fine septations were seen in the cystic component of the
mass (Fig. 1B). The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. The hysterectomy specimen showed an irregular multilocular cystic mass attached to the uterine fundus (Fig. 1C). Microscopic examinations found multiple mesothelium-lined cysts surrounded by a fibrovascular stroma with adenomatoid changes (Fig. 1D). The pathologic diagnosis was multicystic mesothelioma of the peritoneum.
Mesotheliomas are mesenchymal neoplasms originating in the serous lining of the pleura, pericardium, or peritoneum. Multicystic mesothelioma of the peritoneum is an intermediate form of mesothelioma: the severity of the disorder is greater than that of the localized, benign adenomatoid mesothelioma but is less than that of the highly lethal form of diffuse epithelial mesotheliomas [1]. Multicystic mesothelioma occurs predominantly (84% of cases) in young or middle-aged women (mean age, 37 years 10 months) [1, 2]. The tumor chiefly affects the pelvic peritoneum, particularly the uterus, cul-de-sac, bladder, and rectum, growing along the serosa as multiple translucent fluidfilled cysts. Multicystic mesothelioma is made up of mesothelium-lined cysts embedded in fibrovascular stroma. The mesothelial cells are typically flattened or cuboidal. In one third of patients, adenomatoid change or squamous metaplasia of the mesothelium is found [1]. Unlike the malignant form of mesothelioma, multicystic mesothelioma has no association with asbestos exposure [1]. The most common presenting symptoms are abdominal pain (46% of patients) and abdominal mass (29% of patients) [2]. In 18% of patients, the tumor is an incidental finding [2].
On sonography, multicystic mesothelioma appears as a multiseptate cystic mass [3]. Typically, CT reveals a well-defined, noncalcified multilocular cystic mass [2], although a case of calcification in a benign cystic peritoneal mesothelioma has been reported [4]. MR imaging shows well-defined lesions that are hypointense on T1-weighted images and have intermediate signal intensity on T2-weighted images, isointense to urine. This finding correlates with the clear watery fluid seen at gross pathologic examination [2].
Differential diagnoses include lymphangioma, endometriosis, ovarian cystadenoma or cystadenocarcinoma, teratoma, pseudomyxoma peritonei, necrotic leiomyoma or leiomyosarcoma, and epithelial inclusion cysts [1, 2]. Because of the rarity of multicystic mesothelioma, a correct preoperative diagnosis is almost never rendered [1]. Multicystic mesothelioma is not chemo- or radiosensitive. No correlation exists between the extent of the tumor and the patient’s survival. Treatment for localized lesions is total surgical excision, and for more extensive lesions, debulking procedures are performed.
Malignant pleural mesothelioma. C. Boutin, M. Schlesser, C. Frenay, Ph. Astoul. ERS Journals Ltd 1998.ABSTRACT: The incidence of malignant pleural mesothelioma (MPM) has risen for some decades and is expected to peak between 2010 and 2020. Up to now, no single treatment has been proven to be effective and death usually occurs within about 12–17 months after diagnosis. Perhaps because of this poor prognosis, early screening has incited little interest. However, certain forms may have a better prognosis when diagnosed early and treated by multimodal therapy or intrapleural immunotherapy. Diagnosis depends foremost on histological analysis of samples obtained by thoracoscopy. This procedure allows the best staging of the pleural cavity with an attempt to detect visceral pleural involvement, which is one of the most important prognostic factors. Although radiotherapy seems necessary and is efficient in preventing the malignant seeding after diagnostic procedures in patients, there has been no randomized phase III study showing the superiority of any treatment compared with another. However, for the early-stage disease (stage I) a logical therapeutic approach seems to be neoadjuvant intrapleural treatment using cytokines. For more advanced disease (stages II and III) resectability should be discussed with the thoracic surgeons and a multimodal treatment combining surgery, radiotherapy and chemotherapy should be proposed for a randomized controlled study. Palliative treatment is indicated for stage IV. In any case, each patient should be enrolled in a clinical trial. Eur Respir J 1998; 12: 972–981.
The term "mesothelioma" was first used in 1921 by EASTWOOD and MARTIN [1]to describe primary tumours of the pleura. At that time, the primary nature of these tumours was controversial without confirmation by autopsy. Today, the histological diagnosis of mesothelioma remains problematic and differential diagnosis against adenocarcinoma is difficult in 10–15% of cases despite the routine use of histochemistry.
The first evidence implicating asbestos in the pathogenesis of mesothelioma was presented in 1960 by WAGNER [2] in South African miners. The incidence of malignant pleural mesothelioma (MPM) has risen for some decades and is expected to peak sometime between 2010 and 2020 [3, 4]. This increase has been attributed to the widespread use of asbestos in the period from World War II until the end of the 1970s [5]. Pleural mesothelioma is more frequent than peritoneal mesothelioma, possibly because in-halation is the usual route of the pathogenic fibres.
No single treatment has been proven to be effective for malignant mesothelioma. Chemotherapy alone has no effect, radiation therapy simply provides palliation against pain, and surgery (even when performed at a relatively early stage) is controversial [6–10]. The value of the current staging system is questionable: after the first classification by BUTCHART et al. [8] the number of successive classifications provides evidence for the difficulty in distinguishing between the various stages of the disease [11–13].
Recent studies have reported good results using immunotherapy and surgery in patients graded as "early stage" according to a new system of classification [14, 15]. The purpose of the present article is to describe the current knowledge on mesothelioma.
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European Respiratory Journal,
Malignant Mesothelioma,
Malignant pleural mesothelioma,
Pleural Mesothelioma
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Case Study
A 10-year-old boy appears at your office with a chief complaint of shortness of breath. Exertional dyspnea has been present for the previous month and is associated with intermittent dry cough. The patient has no associated fever, chills, or chest pain. Chart review indicates no history of asthma or other pulmonary disease, although the patient has been seen several times for “hay fever.”
The patient is accompanied by his mother, who appears quite anxious. The mother emotionally relates that her 65-year-old cousin has recently been diagnosed with mesothelioma and is dying. Furthermore, he had been a custodian at the patient’s school for the previous 3 years, after retiring from his career as a longshoreman. His work at the school involved general cleanup and boiler room maintenance. The mother is afraid that her son’s dyspnea and cough are related to asbestos exposure at the school and that he might be developing mesothelioma, because he often helped her cousin after school. Recent asbestos removal in the school boiler room has increased the mother’s concern.
On physical examination, the patient is in no acute distress. Respirations are unlabored. Lung auscultation reveals a diffuse, expiratory wheeze. Spirometry performed in the office shows a forced vital capacity (FVC) of 95% of predicted value and a forced expiratory volume in 1 second (FEV1) of 88% of predicted value, with an FEV1/FVC of 70%. The remainder of the examination is within normal limits. A chest radiograph is normal.
1. PURPOSEThis procedure addresses two issues relating to asbestos containing materials (ACMs): ACM found in equipment and parts and ACM found in building materials. The proper procedure for the handling of ACM such as gaskets, set screw packing, geothermal valve packing, geothermal wellhead casing packoff materials, and other potential ACMs found in equipment being repaired, refurbished, or scrapped is discussed along with procedures for handling asbestos in building materials.
This procedure is designed to ensure that employee exposure to asbestos fibers is minimized or eliminated and that ACM is removed, stored, and disposed of properly during the repair, refurbishment, or scrapping of equipment. In addition, procedures are established for preparing for demolition or renovation activities in buildings, shops, warehouses, and other structures that may contain ACM.
2. SCOPE
This procedure applies to all Company employees and contractors who may come into contact with ACM while performing work on equipment. This procedure also addresses demolition or renovation activities in structures or buildings that contain
ACM as defined in the Asbestos NESHAP (40 CFR Part 61, Subpart M).
NOTE: It is the policy of COMPANY that no demolition or renovation activities occur in any owned or leased office buildings, warehouses, shops, or other buildings without the prior approval of the HSE Department. Under no circumstances shall any employee or contractor hired by COMPANY demolish or renovate building materials without first obtaining approval from the HSE Department. Approval will be dependent upon sampling and analysis of the building materials planned for renovation.
3. RESPONSIBILITIES
3.1 Department Supervisor or District Manager
a. Understand this procedure and communicate the information in the procedure to employees.
b. Train employees on the hazards of asbestos and ACM work procedures.
c. Ensure no renovation or demolition activities occur to building materials without prior approval.
d. Ensure ACM is properly stored and disposed of according to state and local regulations.
3.2 HSE Coordinator
a. Identify gasket and packing materials that are ACM through sampling and analysis or review of purchased materials.
b. Assist Department Supervisor or District Manager with implementation of this procedure, including training and proper disposal of ACM.
Thursday, October 14, 2010
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Asbestos,
Asbestos Containing Materials,
Disposal,
Procedure
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