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Benign mesothelioma is a rare, nonmalignant tumor originating from mesothelial cells that line various organ surfaces, most frequently found in the pleura but also occurring in the peritoneum, pericardium, and other tissues. Unlike malignant mesotheliomas, benign forms have no established link to asbestos exposure. However, they may develop in response to other stimuli, such as mechanical injury or inflammation. Patients typically present with nonspecific symptoms, including abdominal pain, chest discomfort, and possible pleural effusion. Imaging studies are helpful to characterize the mass, but a definitive diagnosis requires surgical resection and histopathologic examination. Complete surgical resection is the mainstay treatment and the most important prognostic determinant for benign mesothelioma, as these patients have a high risk of local recurrence if excision is incomplete. This activity for healthcare professionals aims to enhance learners' competence in selecting appropriate diagnostic tests, managing benign mesotheliomas, and fostering effective interprofessional teamwork to improve outcomes. Objectives: Identify the histopathological features of a benign mesothelioma. Evaluate benign mesothelioma with the most appropriate diagnostic studies. Select the optimal treatment strategy for benign mesothelioma. Implement care coordination strategies among interprofessional team members to improve outcomes for patients affected by benign mesothelioma. Access free multiple choice questions on this topic.

Mesotheliomas are a proliferative neoplasm that arises from the mesothelium's epithelial and mesenchymal cells, which comprise part of the serosal covering and lining of various organ surfaces within the body. These tumors most commonly occur in the pleura but may be found in other areas, including potentially soft tissues, viscera, the peritoneum, meninges, and pericardium.[1][2] Mesotheliomas can broadly divide into benign and malignant types. Although they are referred to as benign, these lesions have demonstrated a high propensity for local recurrence after removal. In some rare cases, there are suspicions that they may undergo malignant transformation.[3] One form of benign mesothelioma is benign multicystic mesothelioma of the peritoneum (BMMP), a rare peritoneal neoplasm that primarily occurs in females.[4] The developmental pathogenesis of these neoplasms is unclear; unlike the malignant counterpart, a relationship to asbestos exposure has not been established. Patients will often present with abdominal pain or abdominal masses, unexpected weight gain, shortness of breath, and pleural effusion.[5] Although imaging studies characterize the mass, resection is necessary for a definitive histopathologic diagnosis.[2] Complete surgical resection is the mainstay treatment and the most important prognostic determinant for benign mesotheliomas.[21]

A clear association exists between malignant mesotheliomas and exposure to harmful substances, eg, asbestos and silica. However, the exact cause of benign mesotheliomas is still somewhat uncertain.[3] Popular theories suggest that their development may be linked to reactive changes, particularly the hyperplasia that mesothelial cells undergo in response to various stimuli. These stimuli include foreign materials, dust, small fibers, and trauma or mechanical injury. Benign pleural mesothelioma has also been thought to develop as a result of radiation therapy administered for other cancers.[6] This injury may lead to the over-proliferation of mesothelial cells and may be associated with metaplasia of the underlying connective tissue, ultimately resulting in a pathological lesion. Additionally, mononuclear cells that adhere to mesothelial surfaces and undergo similar differentiation may contribute to the formation of these lesions.[7] These lesions are also observed in patients with inflammatory diseases.[8]

Benign mesotheliomas are a rare entity, much rarer than their malignant counterpart. According to one review study, the incidence of multicystic peritoneal types of benign mesothelioma is 0.15 of 100,000 individuals annually.[9] Benign multicystic mesotheliomas are more common in women in their 20s to 40s and may correlate with endometriosis and pelvic inflammatory disease. Multicystic peritoneal mesothelioma typically accounts for over 5% of peritoneal mesothelioma.[10] Males who develop benign mesotheliomas are usually older, with a mean age of 67 years. Because the disease is rarer in males than females, epidemiologic data suggesting possible associations is lacking. A potential link to the history of previous abdominal surgeries has been reported in females who develop benign mesotheliomas. Cadmium has also demonstrated an association with the development of mesotheliomas. Social risk factors for developing benign mesotheliomas include alcohol use and smoking history; other risk factors include a history of trauma and a family history of benign mesothelioma.[11][1]

Accurate diagnosis of benign mesothelioma requires the interpretation of hematoxylin and eosin staining in conjunction with immunohistochemistry and molecular markers.[12] Additionally, the diagnosis must align with the relevant clinical, radiologic, surgical, and gross findings. Ensuring that the biopsy or specimen is sufficient in both quantity and representation of the lesion to make a reliable diagnosis is also critical. Cellular mesothelial proliferations can exhibit various histological appearances and should always be approached cautiously, as small biopsies may not adequately represent the entire mass or lesion. Histologic Features Benign or reactive mesothelial proliferations can exhibit concerning features typically associated with malignant, atypical, or dysplastic neoplasms, such as increased cellularity, cytological atypia, elevated mitotic activity, papillary formations, and even necrosis. Another misleading feature that could incorrectly suggest malignancy is the presence of increased fibrosis surrounding benign mesothelial cells, which may mimic invasion. One of the most helpful distinguishing histological characteristics of malignancy is the presence of true invasion. Invasion can be focal and may be difficult to identify. In such cases, keratin stains can be useful to highlight invasive cells residing deep within the stromal tissue.[13] Features more commonly seen in mesothelial hyperplasia or benign mesothelioma include a lack of invasion and no increased cellularity within the stroma. If papillary formations are present, they should be simple, small to medium in size, and lined by a single layer of cells with only mild to moderate atypia exhibiting uniform growth. Inflammation is often present, and while necrosis has been reported in association with benign mesothelial proliferations, it should be a rare and focal finding when observed. Pathologists frequently hesitate to diagnose benign mesothelial proliferation based solely on cytology; they prefer permanent tissue examination due to the rarity of these samples and the need for sufficient material.[13]

Features more commonly seen in mesothelial hyperplasia or benign mesothelioma include a lack of invasion and no increased cellularity within the stroma. If papillary formations are present, they should be simple, small to medium in size, and lined by a single layer of cells with only mild to moderate atypia exhibiting uniform growth. Inflammation is often present, and while necrosis has been reported in association with benign mesothelial proliferations, it should be a rare and focal finding when observed. Pathologists frequently hesitate to diagnose benign mesothelial proliferation based solely on cytology; they prefer permanent tissue examination due to the rarity of these samples and the need for sufficient material.[13] Some indicators that assist in the histological diagnosis of malignant mesothelioma in cytology preparations include an increased nuclear-to-cytoplasmic ratio with hyperchromatic nuclei. Some cytopathologists describe these enlarged nuclei as "pushing" against the cytoplasm. Cytology specimens from pleural effusions may display abundant cellularity, predominantly composed of atypical appearing mesothelial cells present in both aggregates and solitary cells. Clinicians should carefully consider alternative causes for atypical histopathological features, as reactive mesothelial cells can appear strikingly atypical, potentially leading to misdiagnosis of malignancy. Molecular Diagnostics With advancements in molecular pathology, one of the more common molecular findings in malignant mesothelioma is the homozygous deletion of the 9p21 locus, which includes the cyclin-dependent kinase inhibitor CDKN2A.[14][15] Additionally, a high level of CA19-9 has been associated with multicystic peritoneal mesothelioma.[10] Research is ongoing to identify ideal biomarkers that can differentiate malignant mesothelioma from benign forms and other malignancies, focusing on their histologies, as well as cellular and subcellular characteristics.[12]

With advancements in molecular pathology, one of the more common molecular findings in malignant mesothelioma is the homozygous deletion of the 9p21 locus, which includes the cyclin-dependent kinase inhibitor CDKN2A.[14][15] Additionally, a high level of CA19-9 has been associated with multicystic peritoneal mesothelioma.[10] Research is ongoing to identify ideal biomarkers that can differentiate malignant mesothelioma from benign forms and other malignancies, focusing on their histologies, as well as cellular and subcellular characteristics.[12] Pulmonary mesothelioma consists of 3 histotypes. The epithelial type is the most common, accounting for 50% to 70% of all cases, followed by the sarcomatoid subtype, which constitutes 10% to 20% of cases and carries the worst prognosis due to its aggressive nature. The third type, termed "biphasic," comprises a mixture of the previous 2 subtypes, with variable activity and prognosis depending on the predominant subtype. Chrysotile, or "white asbestos," is the causative agent in 99% of lung cases, with a latency period of up to 50 years. Given the intensive nature of mesothelioma treatment, differentiating benign traits from those suggesting malignancy is essential. Genetic studies indicate that the most significant chromosomal changes occur on chromosomes 3, 9, and 22. The corresponding genes include BPAP1 (3p21; involved in DNA repair), CDKN2A (9p21; tumor suppressor proteins p16-INK4A and p14-ARF), and NF2 (22q12, affecting various targets including Moesin-Ezrin-Radixin-like protein and MTOR, a cellular metabolic regulator). Alterations at any of these sites can lead to the loss of tumor suppressor activity and contribute to tumor progression and malignant degeneration. Studies involving microRNAs (miRNAs) indicate that their downregulation reduces suppressor effects on proto-oncogenes, including BCL-2, OCT4, MCL-1, and miR-31.

Given the intensive nature of mesothelioma treatment, differentiating benign traits from those suggesting malignancy is essential. Genetic studies indicate that the most significant chromosomal changes occur on chromosomes 3, 9, and 22. The corresponding genes include BPAP1 (3p21; involved in DNA repair), CDKN2A (9p21; tumor suppressor proteins p16-INK4A and p14-ARF), and NF2 (22q12, affecting various targets including Moesin-Ezrin-Radixin-like protein and MTOR, a cellular metabolic regulator). Alterations at any of these sites can lead to the loss of tumor suppressor activity and contribute to tumor progression and malignant degeneration. Studies involving microRNAs (miRNAs) indicate that their downregulation reduces suppressor effects on proto-oncogenes, including BCL-2, OCT4, MCL-1, and miR-31. BRCA-associated protein 1 (BAP1) immunostaining interacts with the BRCA1-BARD complex, which is crucial for DNA repair. Although BAP1 negativity has been linked to the development of mesothelioma in situ, other biomarkers, eg, fibulin-3, miRNAs, and mesothelin, have shown some utility in diagnosis.[12][16] Other immunohistochemical indicators of a benign diagnosis may include desmin positivity. In contrast, markers, eg, EMA, p53, GLUT-1, and IMP-3, may suggest malignancy. Notably, keratin can be positive in both benign and malignant mesothelial cells.[17] Benign mesotheliomas typically stain positive for calretinin and D2-40.[1]

Patients with benign mesothelial proliferations may experience abdominal masses or a feeling of fullness in the abdomen, abdominal pain, chest pain (with or without pleural effusions), unexpected weight gain, and other nonspecific symptoms. Notably, if a patient presents with a pleural effusion that is found to be hemorrhagic, considering the possibility of a malignant process, eg, mesothelioma, rather than a benign condition is critical.[17] However, clinicians should also remember that other potential causes for hemorrhagic effusions (eg, trauma and pneumonia) must be excluded.[18] If the mesothelial proliferation becomes sufficiently large, patients may report experiencing shortness of breath, intestinal obstruction, reflux symptoms, or urinary issues.[17]

Imaging Studies Imaging studies primarily include computer tomography (CT), ultrasound, and magnetic resonance imaging (MRI), which help to identify tumor location, the complexity of the mass, and the tumor's relationship to surrounding structures. The findings of these studies are similar to other soft-tissue masses with a well-circumscribed, homogenous tumor that appears enhanced, likely due to the lesion's vascularity being common.[19] MRI is often utilized to differentiate the mass from adjacent structures. For large chest masses, MRI may also be beneficial in identifying whether any vertebrae are involved or if evidence of hemorrhage or necrosis is present.[13] Additional Diagnostic Studies If a pleural effusion is present, fluid aspiration with chemical, microbiological, and cytopathologic analysis should be considered. These studies can lend diagnostic clues as to the cause of the effusion. Ultimately, resection of the mass is necessary for a definitive histopathologic diagnosis.[2] Molecular analysis is also becoming increasingly useful to guide diagnosis.[20] After a tissue sample has been obtained, BAP1 immunohistochemistry is an effective methodology to determine if the mesothelial proliferation is benign or possibly malignant. Loss of BAP1 immunostain has shown excellent specificity in differentiating a malignant versus a benign mesothelial process. Importantly, loss of BAP1 expression or CDKN2A homozygous deletion should flag any mesothelial process as possibly malignant, as these findings are not routinely encountered in benign mesothelial processes.[21][22] One of the ways that benign and malignant mesotheliomas can present is through a pleural effusion, so evaluation of the effusion with certain laboratory parameters may be of use. If mesothelioma is suspected as the cause of a pleural effusion, laboratory indicators that could support the notion that a suspicious pleural effusion is not from malignant mesothelioma would be low levels of fibulin-3, mesothelin, and vascular endothelial growth factor.[23] Additionally, if aquaporin-1 is expressed in the tissue, this finding could represent that mesothelial proliferation is malignant in nature. Oddly, though, if aquaporin-1 is expressed in malignant mesothelioma, this finding may actually be a favorable prognostic indicator, with patients showing increased survival.[24][25][26]

Resection is typically regarded as an appropriate treatment for benign mesotheliomas. However, local recurrence is common when the mass is not entirely excised. For certain variants, including benign cystic mesothelioma of the peritoneum, some experts recommend a more aggressive surgical approach, which may include heated intraperitoneal chemotherapy, to reduce the risk of recurrence.[3]

Any neoplasms of organs affected by mesotheliomas should be considered in the differential diagnosis, including but not limited to malignant mesothelioma, pleural lipomas, sarcomas, malignant fibrous tumors of the pleura, and localized fibrous tumors of the pleura. Although lymphomas involving the pleura are quite rare, they can occur. This list is not exhaustive; clinicians should remember that malignant mesotheliomas are more common than benign ones. If mesothelioma is suspected, distinguishing between benign and malignant forms is arguably the most crucial consideration. Radiological exams may not reliably differentiate between benign and malignant forms of mesotheliomas or pleural neoplasms. Additionally, while less relevant in the United States, hydatid cysts should be included in the differential diagnosis in the global population, especially if a biopsy (eg, fine needle aspiration) is being considered, as rupturing a hydatid cyst can result in anaphylaxis.[27][1][28][29]

The prognosis for benign mesotheliomas is generally quite favorable if the lesion is completely surgically removed. However, recurrences are common and also necessitate complete excision. Currently, no definitive risk factors for recurrence have been identified.[8] Recent literature has suggested the use of adjuvant therapy for multicystic peritoneal mesothelioma.[10] Additionally, experts recommend implementing hyperthermia and intraperitoneal therapy, which includes cisplatin and doxorubicin, following cytoreductive surgery. The recurrence rate after resection alone is approximately 50%, whereas with the addition of adjuvant therapy, the rate decreases to about 20%.

Although benign mesothelioma is typically not problematic in the long term, complications can arise after surgery despite it being a relatively harmless condition. The most common complication is fluid accumulation in the pleural spaces, which can lead to pressure on the lungs and heart. In such cases, treatment involves surgically removing the excess fluid and placing a fitted chest drain to prevent further fluid buildup and effusion.[30][31]

While surgical treatment is relatively straightforward, clinicians should inform patients regarding potential surgical risks, the potential for recurrence, and the very rare possibility of malignant transformation.

Benign mesotheliomas are a rare entity and, as such, require effective care involving various healthcare professionals. Effective management of benign mesothelioma requires the coordinated skills and responsibilities of an interprofessional team to enhance patient-centered care, improve outcomes, ensure patient safety, and optimize team performance. Physicians, advanced practitioners, and radiologists play essential roles in evaluating diagnostic imaging and conducting procedures such as ultrasound-guided thoracentesis to characterize pleural effusions. Collaboration with pathologists utilizing molecular analyses is vital in differentiating benign from malignant mesothelial proliferations—a challenging distinction even for experts. Surgeons, supported by anesthesiology staff, nurses, and technicians, aim for complete resection to minimize recurrence risks while reducing morbidity and mortality. Clear interprofessional communication and care coordination among all team members, including pharmacists for medication management, foster a seamless approach to diagnosis, treatment planning, and follow-up, which is essential given the complexity and rarity of benign mesotheliomas.