NORD is very grateful to Joseph R. Testa, Ph.D., FACMG, Carol & Kenneth Weg Chair in Human Genetics, Cancer Biology Program Co-Leader, Genomics Facility Director, Fox Chase Cancer Center, for assistance in the preparation of this report.
Synonyms of Mesothelioma
- malignant mesothelioma
- malignant pericardial mesothelioma
- malignant peritoneal mesothelioma
- malignant pleural mesothelioma
Mesothelioma is a rare form of cancer that affects the cells that make up the mesothelium. The mesothelium is the lining or membrane that covers and protects various internal organs of the body. The mesothelium is composed of two layers of specialized cells known as mesothelial cells. One layer directly surrounds an organ; the other forms a protective sacs around thoracic and peritoneal organs. The most common form of mesothelioma affects the pleura, which is the membrane or sac that lines the lungs and chest cavity. Other common sites include the peritoneum, which is the membrane lining the abdominal cavity, and the pericardium, which is the membrane lining the heart (heart sac). Mesothelial tissue is also found in other areas of the body including the membrane covering the testicles (tunica vaginalis). The disorder most often occurs in older adults. Mesothelioma is often an aggressive form of cancer. Treatments are available, but are not effective for everyone.
The term "cancer"refers to a group of diseases characterized by abnormal, uncontrolled cellular growth (e.g., mesothelial cells) that invades surrounding tissues and may spread (metastasize) to distant bodily tissues or organs via the bloodstream, the lymphatic system, or other means. Different forms of cancer, including mesothelioma, may be classified based upon the cell type involved, the specific nature of the malignancy, the tissues or organs affected, and the disease's clinical course. Symptoms of mesothelioma vary depending upon the location, type and stage of the cancer. Approximately 70 to 90% of cases of mesothelioma result from exposure to asbestos. Symptoms of mesothelioma may not appear until up to 30 to 50 years after initial exposure to asbestos. However, after symptoms become apparent, mesothelioma may rapidly progress to cause life-threatening complications.
The symptoms of mesothelioma vary depending upon the location, type and stage of the cancer. Unfortunately, early in the course of the disease, many people have no symptoms, and the tumor can be difficult to see on X-ray examination.
In approximately 85% of patients, mesothelioma arises in the membranes surrounding the lungs (malignant pleural mesothelioma). A collection of fluid around the lung, termed a pleural effusion, may be present. Symptoms may include shortness of breath or difficulty breathing (dyspnea), chest pain, or a chronic cough due to pleural effusion. Difficulty swallowing (dysphagia) can also occur, but is usually a late complication. A mass in the chest wall or unusual lumps of tissue under the skin of the chest may develop in some cases.
When the membrane surrounding the stomach is affected (peritoneal mesothelioma), symptoms may include unexplained weight loss, stomach (abdomen) pain, nausea, vomiting, diarrhea, loss of appetite, low levels of circulating red blood cells (anemia), and abnormal accumulation of fluid in the space (peritoneal cavity) between the two layers of the membrane (peritoneum) that lines the stomach (ascites). Small bowel obstruction may occur, usually as a late complication of the disorder.
When the membrane surrounding the heart is affected (pericardial mesothelioma), heart rhythm abnormalities or low blood pressure may occur. Chest pain and breathing difficulties can also occur with pericardial mesothelioma.
Individuals with mesothelioma may also experience general symptoms including fever, weakness, night sweats, unexplained weight loss, and a general feeling of ill health (malaise).
In extremely rare cases, mesothelial tissue lining the testicles can give rise to mesothelioma. This tissue is part of the peritoneal mesothelium that extends into the scrotum.
Researchers speculate that genetic and immunologic abnormalities, environmental exposures, and/or other factors may play contributing roles in causing specific types of cancer such as mesothelioma.
Approximately 70 to 90% of affected individuals have a significant history of asbestos exposure making it the major associated risk factor for the development of mesothelioma. Asbestos is a fibrous material that is resistant to fire, resulting in its use as insulation and in fire safety products. Asbestos was also used in the production of a wide variety of products including brake linings, roofing products, floor tiles, and cement. Asbestos production and use peaked in the United States during the 1930s-1960s and slowly tapered off during the 1970s. Most use of asbestos stopped after 1989. Asbestos is associated with the development of mesothelioma when asbestos fibers are inhaled or swallowed and attach to tissues lining the respiratory and/or digestive tracts.
There are different types of asbestos fibers such as serpentine fibers, which are long and curvy, and amphibole fibers, which are straight and needle-like. Serpentine fibers, due to their shape, are more easily cleared from the lungs. Crocidolite fibers, which are a subtype of amphibole fibers, are most commonly associated with mesothelioma in humans.
The most common form of asbestos exposure is occupational exposure, in which a person is exposed because of their job. The list of potential jobs is long and extensive because of the widespread use of asbestos in the past. In addition to occupational exposure, both para-occupational and non-occupational exposure has been linked to mesothelioma. Para-occupational exposure is when a person is exposed to asbestos from another person who is exposed through their work. For example, people who are exposed to asbestos at work may bring the fibers home on their clothes exposing their spouses. After a few years of this secondary exposure, there is an increased risk of the spouse developing mesothelioma.
Although asbestos is the major risk factor for developing mesothelioma, asbestos exposure alone does not account for every case. Causes of non-asbestos related mesothelioma have been suggested. A volcanic mineral, known as erionite, can also cause mesothelioma. Erionite was first linked to the disorder because of a greatly increased incidence of mesothelioma in Cappadocia, in the central Anatoli region of Turkey. Researchers believe that genetic factors in the native population play a significant role in the increased prevalence of the disorder in this region. However, to date, a genetic factor has not been identified in Cappadocia. Erionite is a fibrous material that belongs to a group of minerals called zeolites. Zeolites are chemically related to asbestos. Erionite is found in the United States, particularly in North Dakota, Western states and often in gravel quarries or road development projects.
In rare cases, individuals develop mesothelioma without asbestos or erionite exposure. The cause in such cases is unknown (idiopathic or spontaneous mesothelioma). In such cases, it is possible that individuals experienced unknown exposure to asbestos or erionite. It is also possible that other causative agents exist that result in the development of mesothelioma such as certain chemicals, radiation, or viruses.
One such example, according to some researchers, is the simian virus 40 (SV40). The SV40 virus may play a role in the development of some cases of mesothelioma although this is controversial. The exact link or relationship between the simian virus 40 and mesothelioma is unknown. Recent studies failed to establish a link, and most researchers in the field have concluded that a causal role does not exit. Much of the evidence for S40 in mesothelioma was derived using polymerase chain reaction (PCR) technique, and newer evidence has shown a high risk of false-positive PCR results owing to the presence of SV40 sequences in common laboratory plasmids.
The exact manner in which exposure to asbestos and other causative agents result in the development of mesothelioma is not fully understood. Some individuals with heavy exposure to asbestos never develop the disorder. Other individuals with limited exposure to asbestos have developed mesothelioma. According to the medical literature, some individuals have developed mesothelioma after only a single exposure to asbestos.
Overall, only a small fraction of individuals exposed to asbestos or other causative agents of mesothelioma actually develop the disorder. Genetics may explain, in part, why some people develop mesothelioma and others do not. Certain genes may result in a genetic predisposition to developing the disorder. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or "activated" under certain circumstances, such as due to a particular environmental factor like the factors described above. People without a genetic predisposition to a disease can still develop the disease, but the risk is much lower.
Specific genes that have been linked to mesothelioma include the tumor suppressor genes BAP1, CDKN2A, and NF2. Inheritance of a mutant copy of the BAP1 gene, which encodes the BRCA1-associated protein, in particular has been shown to convey a greatly increased risk of developing mesothelioma as well as ocular (uveal) and skin melanomas, carcinomas of the kidney and other organs, and benign melanocytic skin tumors. Somatic (acquired) mutations of BAP1, NF2 and CDKN2A (which encodes both p16INK4A and p14ARF), occur frequently in both sporadic (non-hereditary) and hereditary forms of mesothelioma.
However, not everyone who has an inherited mutation of BAP1 will develop mesothelioma. Some individuals who carry a germline mutation BAP1 develop one of more of the other tumor types connected with the BAP1 syndrome. Some BAP1 mutation carriers have developed only benign skin tumors, and others have developed no tumors to date. Long-term studies of such individuals are needed to assess cancer susceptibility over a lifetime. Notably, a mouse model carrying a germline BAP1 mutation was reported to be much more susceptible to the development of asbestos-induced mesotheliomas than similarly exposed siblings that did not carry the mutation. Notably, no spontaneous mesotheliomas were seen in BAP1 mutation carriers or genetically normal siblings that were not exposed to asbestos.
Importantly, in humans, the vast majority of all mesotheliomas occur in individuals who do not have a BAP1 mutation. This suggests that additional factors may be necessary for the development of the disorder. More research is necessary to understand the complex genetic factors that contribute to the development of mesothelioma.
Mesothelioma can affect individuals of any age although it occurs most often in individuals 50 years or older. According to data compiled from the U.S. Surveillance Epidemiology and End Results (SEER) program between the years 1973-1992, there has been a consistently higher rate of mesothelioma in men than in women. Approximately 3,000 new cases of mesothelioma are diagnosed in each year in the United States, and many more may be misdiagnosed or under-reported. As stated above, individuals with a history of asbestos exposure are at greatest risk for this disease.
The lining of the chest cavity and lungs (pleura) is the most common site for mesothelioma, accounting for more than 85% of cases. The lining of the stomach (peritoneum) is the second most common site and accounts for approximately 10% of all cases. Approximately 250 new cases of peritoneal mesothelioma occur every year in the United States.
The exact incidence or prevalence of mesothelioma is unknown, but the disorder has been estimated to account for less than 1% of all forms of cancer. The incidence of mesothelioma that develops without known exposure to asbestos is approximately 1 in 1,000,000 in the general population.
Symptoms of the following disorders can be similar to those of mesothelioma. Comparisons may be useful for a differential diagnosis:
Other malignant forms of cancer may be confused with mesothelioma including adenocarcinoma, which may arise in the lungs or other areas and spread to the lining of the chest (pleura). Forms of lymphoma, myeloma, thymoma, and leukemia may also have similar symptoms to mesothelioma. Pneumonia may mimic some of the early signs of mesothelioma. Pulmonary fibrosis, pulmonary embolism, lung infections and other lung diseases may need to be differentiated from mesothelioma.
A diagnosis of mesothelioma is made based upon a thorough clinical evaluation, a detailed patient history, characteristic symptoms and physical findings, a variety of specialized tests including chest X-rays, blood tests, and tests that determine lung function. Specialized imaging techniques may also be used to help evaluate the size, placement, and extension of the mesothelioma.
Clinical Testing and Work up
Specialized imaging techniques may include computerized tomography (CT) scanning and positron emission tomography (PET) scan. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures and can reveal the entire pleural surface. During a PET scan, three-dimensional images are produced that reflect the brain’s chemical activity.
Less often, magnetic resonance imaging (MRI) may be used. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. An MRI can provide additional information about mesothelioma in individuals who are candidates for surgery.
A diagnosis of mesothelioma will usually need to be confirmed by the surgical removal and microscopic examination (biopsy) of affected tissue. Different types of biopsies (e.g., transthoracic needle biopsy, needle-assisted thoracoscopy) may be performed. Needle biopsy of mesothelioma may be performed by a radiologist using either ultrasound or a CT scan to guide placement of the needle. During video thoracoscopy, a thin tube with a built-in camera (thoracoscope) is inserted into the chest through a small surgical cut (incision) allowing a physician to view the lungs and obtain tissue samples. This is usually a formal operative procedure performed in an operating room, or similar setting, and may require a general anesthetic with a temporary breathing tube. A similar procedure called a laparoscopy may be performed to view the peritoneum lining the inside of the stomach. Only in rare cases, will a needle biopsy, a thoracoscopy, or laparoscopy not obtain enough tissue for diagnosis. In these cases, more invasive techniques such as a thoracotomy or laparotomy (operative procedures with larger incisions), may be performed to assist in the diagnosis of mesothelioma.
When an individual is diagnosed with mesothelioma, assessment is also required to determine the extent or “stage” of the disease. Staging is important to help determine how far the disease has spread, characterize the potential disease course, and determine appropriate treatment approaches. Some of the same diagnostic tests described above may be used in staging mesothelioma. In addition, even when the disease is limited to the chest, a physician may need to perform a procedure called a mediastinoscopy (similar to other techniques above) to take biopsies of lymph nodes in the central region (mediastinum) of the chest, or laparoscopy to rule out spread into the abdomen as radiographic tests may miss disease in these areas. There is no consensus staging system for mesothelioma; at least six different staging systems have been proposed in the medical literature.
The therapeutic management of individuals with mesothelioma may require the coordinated efforts of a team of medical professionals, such as physicians who specialize in the diagnosis and treatment of cancer (medical oncologists), specialists in the use of radiation to treat cancer (radiation oncologists), surgeons, oncology nurses, and other specialists (depending upon the primary tumor site). Psychosocial support for the entire family is essential as well.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as primary tumor location, extent of the primary tumor (stage), and degree of malignancy (grade); whether the tumor has spread to lymph nodes or distant sites; individual's age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors. As this is an unusual disease, patients should give strong consideration to seeking the care of a specialist in this area, preferably at a major medical center that has extensive experience treating this very challenging disease.
In many individuals with mesothelioma, standard therapy includes surgical removal of all or a portion of the malignancy and affected tissue. Surgical removal of the lining of the chest (pleura) may be performed in some cases of pleural mesothelioma (pleurectomy). Another procedure, known as an extrapleural pneumonectomy involves surgical removal of the pleura, pericardium, diaphragm, and the entire affected lung. Surgical removal of the peritoneum and surrounding tissue may be performed in cases of peritoneal mesothelioma. Surgery may also be performed to remove fluid accumulation from the chest or abdomen in order to relieve pain and other symptoms.
In addition, based upon primary tumor site, size, and other factors, recommended therapy may often include postoperative radiation to help treat known or possible residual disease. If initial surgery is not an option due to the specific location and/or progression of the malignancy, therapy may include radiation alone. Radiation therapy preferentially destroys or injures rapidly dividing cells, primarily cancerous cells. However, some healthy cells (e.g., hair follicles, bone marrow, etc.) may also be damaged, leading to certain side effects. Thus, during such therapy, the radiation is passed through diseased tissue in carefully calculated dosages to destroy cancer cells while minimizing exposure and damage to normal cells. Radiation therapy works to destroy cancer cells by depositing energy that damages their genetic material, preventing or slowing their growth and replication. Various types of radiation may be used--again, depending on cancer type, location, stage and grade, prior treatments.
For some affected individuals, particularly those who have locally advanced, metastatic, or recurrent disease, or those unable to tolerate more aggressive approaches, therapy with certain anticancer drugs (chemotherapy) may also be recommended. Combination chemotherapy is generally more effective than treatment with a single agent, and physicians may recommend combination therapy with multiple chemotherapeutic drugs that have different modes of action in destroying tumor cells and/or preventing them from multiplying.
For some patients, some combination of two or all three treatment modalities (surgery, radiation, chemotherapy) may be considered. This is known as the multimodal approach.
In February 2004, the U.S. Food and Drug Administration (FDA) approved the orphan drug pemetrexed disodium (Alimta) used in combination with cisplatin for the treatment of individuals with malignant pleural mesothelioma when surgery is not an option. Alimta is distributed by Eli Lilly and Company.
Some treatment for individuals with mesothelioma may help to reduce symptoms and ease pain. Such therapies include procedures known as thoracentesis and paracentesis to drain fluid that may accumulate in the chest or stomach. During a thoracentesis, a needle or small tube (catheter) is inserted into the chest to remove excessive fluid. During a paracentesis, a small, thin tube is inserted into the stomach.
Various studies have aimed to develop new or novel therapies for treating mesothelioma including immunotherapy, gene therapy, new chemotherapeutic drugs and/or new combinations of chemotherapeutic drugs. Immunotherapy is the enhancement or suppression of the body’s immune system to fight disease such as cancer. Gene therapy for cancer treatment can include ‘suicide’ or cytokine gene therapy. Suicide gene therapy involves the transfer of a gene (transduction) into tumor cells. This gene produces an enzyme that creates sensitivity in the tumor cells to an otherwise benign therapeutic drug. This enzyme results in the accumulation of a toxic metabolite that causes cell death (‘suicide’). Cytokine gene therapy involves the transfer of a gene that produces a cytokine, which is a small protein that helps to regulate communication among the cells of the immune system or between cells of the immune system and cells of another tissue. Cytokine gene therapy is designed to stimulate the immune system to destroy cancer cells. More research is necessary to determine the long-term safety and effectiveness of novel therapies for the treatment of individuals with mesothelioma.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
NORD Member Organizations:
(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at firstname.lastname@example.org.)
Xu J, Kadariva Y, Cheung M, et al. Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma. Cancer Res. 2014;[Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/24928783
Opitz I. Management of malignant pleural mesothelioma – the European experience. J Thorac Dis. 2014;6:S238-S252. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032963/?report=classic
Porpodis K, Zarogoulidis P, Boutsikou E, et al. Malignant pleural mesothelioma: current and future perspectives. J Thorac Dis. 2013;5:S397-S406. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791499/
van Zandwijk N, Clarke C, Henderson D, et al. Guidelines for the diagnosis and treatment of malignant pleural mesothelioma. Thorac Dis Dec. 2013;5:E254-E307. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886874/
Haas AR, Sterman DH. Malignant pleural mesothelioma: update on treatment options with focus on novel therapies. Clin Chest Med. 2013;34:99-111. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612173/
Mossman BT, Shukla A, Heintz NH, et al. New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas. Am J Pathol. 2013;182:1065-1077. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3657618/
Ladanyi M, Zauderer MG, Krug LM, et al. New strategies in pleural mesothelioma: BAP1 and NF2 as novel targets for therapeutic development and risk assessment. Clin Cancer Res. 2012;18:4485-4490. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432735/
Donovan EP, Donovan BL, McKinley MA, Cowan DM, Paustenbach DJ. Evaluation of take home (para-occupational) exposure to asbestos and disease: a review of the literature. Crit Rev Toxicol. 2012;42:703-707. http://www.ncbi.nlm.nih.gov/pubmed/22913651
Testa JR, Cheung M, Pei J, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43:1022-1025. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3184199/
Gregoire M. What’s the place of immunotherapy in malignant mesothelioma? Cell Adh Migr. 2010;4:153-161. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852572/
Moore AJ, Parker RJ, Wiggins J. Malignant mesothelioma. Orphanet J Rare Dis. 2008;3:34. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652430/
Vachani A, Sterman DH, Albelda SM. Cytokine gene therapy for malignant pleural mesothelioma. J Thorac Oncol. 2007;2:265-267. http://www.ncbi.nlm.nih.gov/pubmed/17409795
Hassan R, Alexander R, Antman K, et al., Current treatment options and biology of peritoneal mesothelioma: meeting summary of the first NIH peritoneal mesothelioma conference. Ann Oncol. 2006;[Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/16600983
Ceresoli GL, Zucali PA, Favaretto AG, et al., Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol. 2006;20:1443-1448. http://www.ncbi.nlm.nih.gov/pubmed/16549838
Vogelzang NJ, Porta C, Mutti L. New agents in the management of advanced mesothelioma. Semin Oncol. 2005;32:336-350. http://www.ncbi.nlm.nih.gov/pubmed/15988688
Wang ZJ, Reddy GP, Gotway MB, et al., Malignant pleural mesothelioma: evaluation with CT, MR imaging, and PET. Radiographics. 2004;24:105-119. http://www.ncbi.nlm.nih.gov/pubmed/14730040
Janne PA., Chemotherapy for malignant pleural mesothelioma. Clin Lung Cancer. 2003;5:98-106. http://www.ncbi.nlm.nih.gov/pubmed/14596692
Smythe W. Current therapy for malignant mesothelioma. Curr Oncol Rep. 2002;4:305-13. http://www.ncbi.nlm.nih.gov/pubmed/12044240
Gordon GJ, Chen CJ, Jaklitsch MT, et al., Detection and quantification of SV40 large T-antigen DNA in mesothelioma tissues and cell lines. Oncol Rep. 2002;9:631-4. http://www.ncbi.nlm.nih.gov/pubmed/11956641
Green MR. The evolving role of gemcitabine and pemetrexed (Alimta) in the management of patients with malignant mesothelioma. Clin Lung Cancer. 2002;3:S26-S29. http://www.ncbi.nlm.nih.gov/pubmed/14720352
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:156240; Last Update:12/20/2011.
Available at: http://omim.org/entry/156240 Accessed May 28, 2014.
Tan WW. Mesothelioma. eMedicine Journal. April 13, 2014. Available at: http://emedicine.medscape.com/article/280367-overview Accessed May 28, 2014.
Dee EK. Malignant Mesothelioma Imaging. eMedicine Journal. April 16, 2014. Available at: http://emedicine.medscape.com/article/359470-overview Accessed May 28, 2014.
National Cancer Institute. Malignant Mesothelioma.
Available at: http://www.cancer.gov/cancertopics/types/malignantmesothelioma Accessed May 28, 2014.
Mayo Clinic for Medical Education and Research. Cervical Dystonia. January 9, 2009. Available at: http://www.mayoclinic.org/diseases-conditions/mesothelioma/basics/definition/con-20026157 Accessed May 28, 2014.
The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.
The National Organization for Rare Disorders (NORD) web site, its databases, and the contents thereof are copyrighted by NORD. No part of the NORD web site, databases, or the contents may be copied in any way, including but not limited to the following: electronically downloading, storing in a retrieval system, or redistributing for any commercial purposes without the express written permission of NORD. Permission is hereby granted to print one hard copy of the information on an individual disease for your personal use, provided that such content is in no way modified, and the credit for the source (NORD) and NORD’s copyright notice are included on the printed copy. Any other electronic reproduction or other printed versions is strictly prohibited.
Copyright ©2004, 2006, 2014
Report last updated: 2014/09/10 00:00:00 GMT+0
NORD's Rare Disease Information Database is copyrighted and may not be published without the written consent of NORD.