Ann Thorac Surg 2004;78:1774-1776
© 2004 The Society of Thoracic Surgeons
Original article: general thoracic
Pleural Biopsy: A Reliable Method for Determining the Diagnosis But Not Subtype in Mesothelioma
Raphael Bueno, MDa,*,
Jason Reblando, BAa,
Jonathan Glickman, MD, PhDb,
Michael T. Jaklitsch, MDa,
Jeanne M. Lukanich, MDa,
David J. Sugarbaker, MDa
a Division of Thoracic Surgery, Boston, MA, USA
b Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA
Accepted for publication May 4, 2004.
* Address reprint requests to Dr Bueno, Division of Thoracic Surgery, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA
rbueno{at}partners.org
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Abstract
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BACKGROUND: Survival after tri-modality therapy with extrapleural pneumonectomy (EPP) and postoperative chemoradiotherapy is longer for patients with epithelial MPM versus mixed or sarcomatoid subtypes, leading some to decline aggressive therapy for patients with nonepithelial histology. However, pathologic diagnosis of malignant pleural mesothelioma (MPM) and subclassification into one of the three histologic subtypes (epithelial, mixed, sarcomatoid) can be challenging. Pleural biopsy has been proposed as the diagnostic gold standard. We investigated the accuracy of open pleural biopsy for diagnosis and subtype identification in MPM.
METHODS: Patients with suspected MPM routinely undergo open pleural biopsy to establish diagnosis. Those diagnosed definitively by pleural biopsy or cytology are offered pleurectomy or EPP dependent on stage and cardiorespiratory status. We reviewed medical records for all patients undergoing EPP at our institution, comparing tissue and subtype diagnosis at initial diagnostic biopsy versus definitive resection.
RESULTS: Between 1988 and 2000, 305 of 332 consecutive patients undergoing EPP had MPM. One patient diagnosed with MPM at pleural biopsy was misclassified. Subtype analysis at pleural biopsy proved correct in 80% (226/282). Most patients (174/192) with epithelial subtype at final diagnosis were diagnosed correctly at pleural biopsy. However, 44% (45/103) with pathologic diagnosis of nonepithelial subtype at resection were initially misdiagnosed with the epithelial subtype. The sensitivity of pleural biopsy for epithelial MPM was 97% with a specificity of 56%.
CONCLUSIONS: Open pleural biopsy is accurate and should be considered the gold standard diagnostic method for MPM. It is less sensitive for determining histologic subclass, particularly with nonepithelial subtypes.
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Introduction
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Malignant pleural mesothelioma (MPM) is a mesodermally derived malignancy of the pleura usually caused by asbestos exposure. Generally resistant to chemotherapy, it is associated with a dismal long-term survival. Approximately 3,000 patients are diagnosed with MPM in the United States annually. The incidence worldwide is projected to continue to rise over the next 20 years [1–6]. The most effective therapy, to date, for patients with early stage disease and adequate cardiorespiratory reserve consists of complete surgical resection of the tumor utilizing extrapleural pneumonectomy (EPP) followed by chemotherapy and radiation therapy (tri-modality approach) [3, 7, 8].
The three common distinct histologic subtypes of MPM based on the microscopic appearance of the predominant malignant elements are: epithelial, sarcomatoid, and mixed (biphasic) [9]. Most MPMs are epithelial (
50%), and this subtype has been associated with somewhat better prognosis. Diagnosis of the mixed subtype often requires a careful and extensive search through multiple blocks of tissue to identify malignant elements of both the epithelial and sarcomatoid types. Unfortunately, the distribution of these two elements may vary in different regions of the tumor [7, 10].
The clinical diagnosis of MPM is often difficult and frequently requires ample tumor tissue for multiple modalities of pathologic diagnosis. Specifically, distinguishing MPM from adenocarcinoma, the more common lung malignancy, is challenging from both a clinical and pathologic perspective [11]. Patients with either disease often present with similar clinical complaints and findings of a unilateral pleural effusion. Given the limitations of fluid cytology in diagnosing MPM [10, 12], sufficient tissue from an open surgical biopsy is usually required for immunohistochemical and cytogenetic analysis to ensure the correct diagnosis [1].
Due to the dismal prognosis of many patients with nonepithelial subtypes of MPM, it may be reasonable to consider excluding them from aggressive tri-modality therapy. To justify such a change in therapeutic approach in the absence of effective alternatives, it must be unequivocally demonstrated that there are no long-term survivors among patients with nonepithelial histology treated with tri-modality therapy, and the diagnostic accuracy of pleural biopsy in assigning histologic subtype is high. To determine the accuracy of tumor diagnosis and histologic subclassification before initiation of tri-modality therapy, we examined the medical records of patients who underwent EPP at Brigham and Women's Hospital.
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Patients and Methods
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The medical records of all patients undergoing EPP at the Brigham and Women's Hospital between 1988 and 2000 were reviewed. For each patient, we examined the operative notes, discharge summary, and all internal and available external pathology and cytology reports. This work was done with the approval of the institution's Man Studies Committee. All pathological diagnoses for each patient undergoing EPP were examined to determine the degree of concordance between the initial diagnosis at pleural biopsy and final diagnosis at EPP with respect to: the primary diagnosis of malignancy (MPM vs non-MPM); and the histologic subtype {epithelial versus nonepithelial). Mixed and sarcomatoid tumors were considered together as nonepithelial. The sensitivity and specificity were determined for the accuracy of each of these diagnoses.
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Results
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Between February 1988 and August 2000, 332 patients (249 males and 83 females) underwent EPP for a variety of thoracic malignancies at the Brigham and Women's Hospital (Table 1). Most patients (188) underwent a right EPP. There were 27 patients who underwent EPP for malignancies other than MPM. These patients had accurate preoperative diagnoses and were not thought to have MPM before their surgery. There were 306 patients with presumed pathologic diagnosis of MPM before EPP, which was based on positive open pleural biopsies in 303 patients. The remaining 3 patients with suspicious but nondiagnostic pleural biopsy had surgery based on clinical grounds and suspicious cytology in specimens from pleural effusions. Of these 306 patients, 305 (99.7%) were found to have MPM at definitive resection. One patient initially diagnosed with MPM at pleural biopsy was found at EPP to have hemangioendothelioma. In this cohort of patients, the positive predictive value of an open pleural biopsy in predicting the diagnosis of MPM is 99.7%.
We examined the sensitivity and specificity of pleural biopsy in predicting the correct histologic subtype of MPM (Table 2). Of 305 patients with the final diagnosis of MPM at EPP, 192 (63%) were classified as epithelial, 101 (33%) as mixed, and 10 (3%) as sarcomatoid. Additionally, 1 patient was classified as desmoplastic and another as mesothelioma with no subtype specified (these last 2 patients are excluded from Table 2). Among the 192 classified as MPM of the epithelial subtype at EPP, 174 (91%) were initially classified as epithelial at pleural biopsy, 5 (3%) were classified as mixed, 12 (6%) were not classified, and 1 patient (0.5%) was determined to be negative for MPM at pleural biopsy but had a positive cytology for MPM. Among the 101 patients diagnosed as mixed MPM at EPP, 45 (44%) were initially diagnosed as mixed, 44 (44%) as epithelial, 4 (4%) as sarcomatoid, 6 (6%) were not classified, and 2 (2%) were negative for MPM at biopsy but with suspicious cytology. Among the 10 patients diagnosed as sarcomatoid MPM at EPP, 7 (70%) were initially classified as sarcomatoid, 2 (20%) as mixed, and 1 (10%) as epithelial subtype. The sensitivity and specificity values of epithelial diagnosis at open pleural biopsy were 97% and 56%, respectively, with a positive predictive value of 79% and a negative predictive value of 92%. Conversely, the sensitivity and specificity values of a nonepithelial diagnosis at open pleural biopsy were 56% and 97%, respectively, with a positive predictive value of 91% and a negative predictive value of 79%.
Three patients initially had a negative pleural biopsy for MPM; however, on clinically suspicious grounds, they were referred for a second biopsy at 4 weeks, 2 months, and 5 months, respectively, after the first biopsy. In all 3 patients, the second biopsy was positive for MPM, and the patients underwent EPP. Pathologic re-examination of two of the initial biopsies suggested that the amount of tissue obtained was probably insufficient. In the third case, proliferation of epithelioid and spindle mesothelial cells without cellular atypia was reported to be most consistent with a benign process.
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Comment
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We evaluated the accuracy of pleural biopsy in the diagnosis of MPM in a consecutive series of 332 patients who underwent EPP for thoracic diseases. All but 1 of 303 patients who were diagnosed with MPM at pleural biopsy had the same diagnosis at EPP. Therefore, the positive predictive value of diagnostic open pleural biopsy obtained preoperatively for MPM is more than 99%. Current diagnostic methods for MPM include closed pleural biopsy, fine needle aspiration, and open pleural biopsy. Closed pleural biopsy performed with a large needle under ultrasound guidance has been reported to correctly diagnose MPM in up to 50% of cases [10]. Cytologic examination of pleural effusion obtained by fine needle aspiration (FNA) has an overall sensitivity between 4% and 69% in various reports [10, 13, 14]. The current study supports the use of open pleural biopsy as the diagnostic method of choice before surgical management of MPM.
Open pleural biopsy for diagnosis of MPM is a brief, simple, and well-tolerated surgical procedure usually performed under general anesthesia requiring only a single lumen endotracheal tube. Thoracotomy with partial pleurectomy is discouraged for the diagnosis of MPM because it may complicate future therapeutic surgery. Through a single 10-mm incision, a mediastinoscope or a video thoracoscope is introduced into the pleural cavity to facilitate biopsy of abnormal pleura under visual guidance. Multiple biopsies [6–12] from many different locations in the suspected tumor are obtained to maximize diagnostic accuracy. The incision is preferably positioned in the line of a posterolateral thoracotomy so that the eventual scar, along with any potential tumor implants, can be excised with the specimen at future surgical resection. A chest tube is placed through the incision at the conclusion of the procedure and usually removed on the next day just before patient discharge. Frozen section diagnosis is generally obtained at the time of surgery to confirm that sufficient diagnostic tissue is available for tumor diagnosis [7, 10]. However, it is often impossible for the pathologist to make a definitive distinction between MPM and lung adenocarcinoma at frozen section because immunohistochemical analysis is usually required for this diagnosis [11]. Therefore, it is important to obtain an adequate amount of tissue that can also be used for cytogenetic and electron microscopy diagnostic analysis.
The current study also demonstrates that the histologic subclassification of MPM based on open pleural biopsy is somewhat inaccurate. Specifically, 20% of tumors initially diagnosed as epithelial were actually nonepithelial (mixed) at EPP and, as a consequence, nearly 45% of patients with true nonepithelial histology were initially diagnosed as having epithelial histology. The mixed subtype contains elements of both spindle and epithelial histologies, and the detection of both histologic elements may be subject to sampling error. Therefore, it is not unreasonable to expect a predominance of one histologic pattern in half of the specimens. We conclude that if the intention of treatment stratification based on histologic diagnosis of MPM is to exclude patients with nonepithelial subtypes from undergoing surgery or other potentially lifesaving therapies, a diagnostic strategy utilizing pleural biopsy is unlikely to be sufficiently accurate.
Occasionally, it can be difficult to distinguish MPM from benign pleural conditions [9, 11, 15]. Six patients had open pleural biopsy without evidence of MPM at some point in the diagnostic process. Three of the 6 patients underwent EPP on the basis of a suspicious cytology, and 3 others underwent EPP after a repeat positive biopsy. We, therefore, recommend close clinical follow up and repeat biopsy for patients who are clinically suspected of having MPM despite an initially negative pleural biopsy.
Although pleural biopsy is the diagnostic strategy of choice for MPM, this technique is substantially less accurate in diagnosing the histologic subtypes of MPM particularly in the case of nonepithelial histology. Consequently, in our view, it is premature to stratify patient treatment based on the histologic diagnosis at pleural biopsy.
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Abstract
Introduction
