benign reactive mesothelial hyperplasia vs neoplasia

Even seasoned surgical pathologists who have established expertise in the diagnosis of malignant mesothelioma (MM) can disagree about whether a pleural biopsy represents MM or atypical epithelioid mesothelial hyperplasia (AEMH).

Clinics

When this question arises, the pathologist is well advised to inquire into the clinical features, radiographic findings, and the surgeon’s assessment of the pleura at the time of biopsy, as this formation can help to clarify questions posed by the morphological findings.

Clinical information to consider in diagnosing a pleural biopsy
• Does patient have a previous diagnosis of malignancy?
• Is the pleural process unilateral?
• Does the patient have a known cause of pleural infection or inflammation?
• Is there a history of occupational or by-stander exposure to asbestos?

If the clinician reports a rapidly developing pleural process or a background of disease that is known to produce pleuritis, the surgical pathologist should be wary of diagnosing MM, in the absence of convincing morphological evidence.

Exudative pleural effusions due to viral infection, parapneumonic effusion, or bacterial empyema, can yield highly AEMH.

Collagen-vascular diseases, including rheumatoid arthritis and systemic lupus erythematosis, may yield organizing fibrinous pleuritis that is easily confused with neoplasia.

Finally, disorders that are generally caused by serous non-inflammatory effusions, including long-standing congestive heart failure, cirrhosis, kidney, and hypothyroidism can also cause difficulties in diagnosis.

Pleural biopsy

The optimal biopsy techniques when MM is a serious diagnostic consideration are either a video-assisted thoracoscopic biopsy (VATB) or open pleural biopsy (OPB).

The attending surgeon’s evaluation of the pleura should be sought whenever the biopsy interpretation is in doubt.

The gross appearance of a pleural surface diffusely studded by tumor and showing infiltration into soft tissues is virtually diagnostic of malignancy and favors diffuse MM. An experienced surgeon will often suggest the diagnosis.

In addition, the surgeon’s assessment that the pleural process is likely benign argues against the diagnosis of malignant mesothelioma.

The number of biopsy samples required to establish the diagnosis of mesothelioma is entirely dependent on the adequacy of sampling.

Multiple biopsies from the most suspicious areas should be harvested, and these should be sufficiently deep to include the endofascial soft tissues of the chest wall.

The number of biopsies is sufficient only when the pathologist can either establish or exclude the diagnosis of malignant mesothelioma with confidence.

Unless clinical contraindications exist, the underlying lung should be sampled, as this can yield information concerning microscopic intrapulmonary extension of MM and the concomitant presence of benign fibroinflammatory disease attributable to asbestos exposure.

Radiology

Knowledge of the radiographic findings can help in distinguishing AEMH from MM. The presence of diffuse or localized masses on conventional radiographs or CT scan favors malignancy.

However, increased tracer uptake on positron-emission tomography (PET) may reflect either benign or malignant disease.

A pleural-based “rind” that compresses the underlying lung and causes a mediastinal shift is characteristic of MM.

Although this appearance can be mimicked by metastatic “pseudomesotheliomatous” adenocarcinoma of the lung, encasement of the lung strongly favors a malignant process.

Radiographic findings in pleural disease
 pleural effusion
 diffuse linear pleural thickening
 diffuse nodular pleural thickening
 localized pleural mass
 calcified hyaline pleural plaques
 rounded atelectasis

Biospy

Ideally, pathologists should play an advisory role in determining the approach to the pleural biopsy, as they will be faced with the challenge of interpretation. The optimal biopsy techniques when MM is a serious diagnostic consideration are either a video-assisted thoracoscopic biopsy or open pleural biopsy.

The attending surgeon’s evaluation of the pleura should be sought whenever the biopsy interpretation is in doubt. The gross appearance of a pleural surface diffusely studded by tumor and showing infiltration into soft tissues is virtually diagnostic of malignancy and favors diffuse MM. An experienced surgeon will often suggest the diagnosis. In addition, the surgeon’s assessment that the pleural process is likely benign argues against the diagnosis of malignant mesothelioma.

The number of biopsy samples required to establish the diagnosis of mesothelioma is entirely dependent on the adequacy of sampling. Multiple biopsies from the most suspicious areas should be harvested, and these should be sufficiently deep to include the endofascial soft tissues of the chest wall. The number of biopsies is sufficient only when the pathologist can either establish or exclude the diagnosis of malignant mesothelioma with confidence. Unless clinical contraindications exist, the underlying lung should be sampled, as this can yield information concerning microscopic intrapulmonary extension of MM and the concomitant presence of benign fibroinflammatory disease attributable to asbestos exposure.

In practice, repeated biopsies may be necessary, in order to establish an unequivocal diagnosis of diffuse MM.

When MM is suspected but the morphological features are insufficient to establish the diagnosis beyond doubt, the biopsy report should be crafted to let the clinician know that continued monitoring and repeat biopsies may be indicated.

For example, an indeterminate biopsy showing severely atypical mesothelial hyperplasia, in the background of occupational exposure to asbestos, clinical, radiographic, or gross findings compatible with MM, should prompt the surgical pathologist to phrase the final diagnosis as “atypical mesothelial hyperplasia without diagnostic features of malignancy, however, mesothelioma cannot be excluded with confidence.” This leads the clinician to consider what, if any, diagnostic tests must be done next.

Adequate sampling is the best way to avoid this awkward situation for the surgeon, pathologist, and most importantly, the patient, who may not understand why an invasive procedure did not yield a definitive diagnosis. But unfortunately, even under the best of circumstances, the definitive diagnosis of MM can be elusive.

Immunochemistry

 desmin

• According to Attanoos and colleagues, the muscle filament protein desmin is strongly expressed in 34/40 (85%) of reactive mesothelial hyperplasia but in only 6/60 (10%) of neoplastic mesothelium.

 EMA

• According to Attanoos and colleagues, epithelial membrane antigen (EMA), a glycosylated membrane protein antigen, is strongly expressed by only 8/40 (20%) of reactive mesothelial cells and by 48/60 (80%) of malignant mesothelium.
• Others have also demonstrated preferential EMA expression by malignant mesothelium ranging from 58% to 100%, with reactive mesothelial cells expressing EMA in 0% to 33% of cases.
• Cury and coworkers noted that EMA staining in malignant mesothelium is generally both strong and diffuse, as opposed to weak and patchy expression by reactive mesothelial cells.

 p53

• Nuclear overexpression of p53, a nuclear phosphoprotein involved in cellular differentiation and turnover, has been linked with neoplasia due to gene mutation on chromosome 17.
• p53 was exclusively expressed by neoplastic epithelium in 40% of cases (27/60) but not by reactive mesothelial cells (0/40) in the Attanoos study.
• However, the range of p53 expression in other studies has been highly variable ranging from 25% to 97% in malignant mesothelium and 45% to 60% in reactive mesothelium.

 BCL2

• Expression of Bcl-2, a 26-kDa protein that interferes with normal programmed cell death, is limited to disorders with high apoptotic rates.
• It has been consistently expressed in less than 10% of malignant mesotheliomas but has not been reproducibly detected in reactive mesothelium, indicating its low sensitivity but high specificity for mesothelial neoplasia.

 XIAP

• Burstein and colleagues recently reported preliminary results that positive immunostaining for XIAP can reliably distinguish benign reactive mesothelial hyperplasia from malignant mesothelioma in a high percentage of cases (USCAP Meeting, 2006).
• The putative role of XIAP immunostaining requires further confirmation.

In summary, the immunoprofile EMA+ (strong), p53+, Bcl-2+, and desmin negative may be interpreted with caution to support a diagnosis of mesothelial malignancy. It must be concluded that there is currently no reproducibly accurate immunohistochemical test that can distinguish benign reactive mesothelial hyperplasia (BRMH) from malignant mesothelioma.

Reviews

 Distinguishing benign mesothelial hyperplasia from neoplasia: a practical approach. Kradin RL, Mark EJ. Semin Diagn Pathol. 2006 Feb;23(1):4-14. PMID: 17044190

 The separation of benign and malignant mesothelial proliferations. Churg A, Galateau-Salle F. Arch Pathol Lab Med. 2012 Oct;136(10):1217-26. PMID: 23020727

 Malignancies in the lung and pleura mimicking benign processes. Colby TV. Semin Diagn Pathol. 1995 Feb;12(1):30-44. PMID: 7770673

 The spectrum of histologic growth patterns in benign and malignant fibrous tumors of the pleura.Moran CA, Suster S, Koss MN. Semin Diagn Pathol. 1992 May;9(2):169-80. PMID: 1609159

References

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 Churg, A., Roggli, V., and Colby, T.V. The separation of benign and malignant mesothelial proliferations. Am J Surg Pathol. 2000; 24: 1183–1200

 Attanoos, R.L., Suvarna, S.K., Rhead, E. et al. Malignant vascular tumours of the pleura in “asbestos” workers and endothelial differentiation in malignant mesothelioma. Thorax. 2000; 55: 860–863

 Henderson, D.W., Shilkin, K.B., and Whitaker, D. Reactive mesothelial hyperplasia vs mesothelioma, including mesothelioma in situ: a brief review. Am J Clin Pathol. 1998; 110: 397–404

 Whitaker, D., Henderson, D.W., and Shilkin, K.B. The concept of mesothelioma in situ: implications for diagnosis and histogenesis. Semin Diagn Pathol. 1992; 9: 151–161

 Mangano, W.E., Cagle, P.T., Chung, A. et al. The diagnosis of desmoplastic malignant mesothelioma and its distinction from fibrous pleurisy: a histologic and immunohistochemical analysis of 31 cases including p53 immunostaining. Am J Clin Pathol. 1998; 110: 191–199

 Attanoos, R.L., Griffin, A., and Gibbs, A.R. The use of immunohistochemistry in distinguishing reactive form neoplastic mesothelium (A novel use for desmin and comparative evaluation with epithelial membrane antigen, p53, platelet-derived growth factor-receptor, P-glycoprotein and Bcl-2) . Histopathology. 2003; 43: 231–238

 Cury, P.M., Butcher, P.N., Corrin, B. et al. The use of histological and imminohistochemical markers to distinguish pleural malignant mesothelioma ans in situ mesothelioma form reactive mesothelial hyperplasia and reactive pleural fibrosis. J Pathol. 1999; 189: 251–257 http://www.ncbi.nlm.nih.gov/pubmed/10547583

 Creaney, J., McLaren, B.M., Stevenson, S. et al. p53 autoantibodies in patients with malignant mesothelioma: stability through disease progression. Br J Cancer. 2001; 84: 52–56 http://www.ncbi.nlm.nih.gov/pubmed/11139313

 Cagle, P.T., Brown, R.W., and Lebovitz, R.M. p53 immunostaining in the differentiation of reactive process from malignancy in pleural biopsy specimens. Hum Pathol. 1994; 25: 443–448 http://dx.doi.org/10.1016/0046-8177(94)90115-5 http://www.ncbi.nlm.nih.gov/pubmed/8200637