Kao SC, Yan TD, Lee K, Burn J, Henderson DW, Klebe S, Kennedy C, Vardy J, Clarke S, van Zandwijk N, McCaughan BC.

Asbestos Diseases Research Institute, Bernie Banton Centre, Sydney, Australia.

Abstract

Introduction: Histological subtype is an established prognostic factor in malignant pleural mesothelioma (MPM). We retrospectively investigated the accuracy of classifying histological subtype on diagnostic biopsies and examined the impact of different diagnostic procedures on the outcome.

Methods: Consecutive patients with histologically confirmed MPM who underwent extrapleural pneumonectomy (EPP) from 1994 to 2009 were included. Patient records were reviewed, and the initial diagnoses of histological subtype were obtained. The archival EPP specimens were reviewed by a panel of pathologists. The histological subtype obtained at review was compared with the initial diagnosis.

Results: Eighty-five patients underwent EPP. Two patients achieved a pathological complete response after neoadjuvant chemotherapy, leaving 83 patients to be included in this review. Different diagnostic methods were used before EPP: 81% thoracoscopy; 7% thoracotomy; 11% computed tomography-guided procedure; and 1% other. Patients determined to have an epithelial subtype (n = 64) at EPP were diagnosed correctly at initial diagnostic biopsy in 84% of cases, whereas patients considered to have a biphasic subtype (n = 19) at EPP were diagnosed correctly at diagnostic biopsy in 26% of cases. The sensitivity and specificity of diagnostic biopsy for epithelial MPM was 93% and 31%, respectively. The overall subtype misclassification rate was 20%. Biopsy by thoracotomy was most accurate in subtype classification (83%) compared with thoracoscopy (74%) and computed tomography-guided procedure (44%).

Conclusions: The determination of histological subtype from a diagnostic biopsy is difficult due to sampling error, but an adequate specimen obtained from surgical biopsy increases the accuracy of subtype classification compared with radiological-guided biopsies.

Demmy TL, Platis IE, Nwogu C, Yendamuri S.

Department of Thoracic Surgery, Roswell Park Cancer Institute, Buffalo, New York.

Abstract

Mesothelioma is the most common primary pleural malignancy. Surgical therapy offers limited cure benefits at the cost of high morbidity. Although technically challenging and performed rarely, a less invasive approach to extrapleural pneumonectomy was developed with the intent to speed convalescence, hasten adjuvant therapies, improve quality of life, and reduce wound surface area for possible tumor contamination.

Zardo P, Zhang R, Wiegmann B, Haverich A, Fischer S.

Department of Thoracic Surgery and Lung Assist, Klinikum Ibbenbüren, Ibbenbüren, Germany.

Abstract

Background: We sought to analyze the efficacy of a bovine pericardial patch (PeriGuard®) for diaphragmatic repair.

Methods: Seven consecutive patients (6 males, median age 56 years) scheduled for diaphragmatic resection and/or repair were enrolled in this study. In all cases diaphragmatic repair was performed with a PeriGuard Repair Patch® (Synovis, St. Paul, MN, USA). At follow-up (median: 12 months; range: 6-18 months), quality of life, signs of reherniation and incorporation of mesh were assessed through clinical examination, blood samples and CT or MRT scan.

Results: Diagnosis on admission included sarcoma (n = 2), mesothelioma (n = 1), squamous cell carcinoma (n = 1), parachordoma (n = 1) and large congenital or posttraumatic herniation (n = 2). At follow-up successful diaphragmatic repair with no signs of reherniation, graft dehiscence or seroma formation was confirmed for all patients. Recorded inflammatory markers [C-reactive protein (CRP), white blood cell count (WBC) and procalcitonin (PCT)] reached their peak values between postoperative day (POD) 4 and POD 7. Values ranged from 122-282 mg/L for CRP, 0.4-4.6 µg/L for PCT and 6.2-15.6 Tsd/µL for WBC. Overall oncological results were good and 5 out of 6 survivors reported a fully reestablished quality of life.

Conclusion: We consider the PeriGuard Repair Patch® a viable alternative to synthetic materials for diaphragm replacement. Moreover, we advise carrying out cautious follow-up in patients undergoing extensive oncological resection to learn more about the biological behavior of the bovine PeriGuard Repair Patch® after diaphragmatic repair.

Lee JM, Pou K, Sadow PM, Chen H, Hu B, Hewison M, Adams JS, Sugarbaker DJ, Fisher ND.

Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. jaymoonlee@mednet.ucla.edu

Abstract

Objective: To report a case of coincident hypercalcemia and Cushing syndrome arising from mesothelioma.

Methods: We describe the clinical, laboratory, imaging, and pathologic findings of a patient with malignant pleural mesothelioma and elucidate the underlying biologic mechanisms resulting in concurrent overexpression of steroid and polypeptide hormones.

Results: A 62-year-old woman presented with chest discomfort and cough. Radiologic imaging revealed a diffuse pleural-based mass encasing the right lung. There was no invasion into the chest wall, diaphragm, or mediastinum, and there was no distant disease. Laboratory analyses documented hypercalcemia and Cushing syndrome, which were due to ectopic overproduction of 1,25-dihydroxyvitamin D (1,25[OH]₂D) and corticotropin. Surgical resection resulted in normocalcemia with normalization of serum 1,25(OH)₂D and reduction in hypercortisolemia. The extrapleural pneumonectomy specimen revealed overexpression of the 1,25(OH)₂D synthetic enzyme 25-hydroxyvitamin-D-1alpha-hydroxylase (1alpha-hydroxylase) and underexpression of the 1,25(OH)₂D catabolic enzyme 24-hydroxylase. Immunohistochemistry and electron microscopy demonstrated corticotropin and secretory granules in the tumor tissue.

Conclusion: These findings support the evidence for a paracrine role of vitamin D in the resistance of the human host to antigen.

Javedan K, Stevens CW, Forster K.

Radiation Oncology,1 H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA. khosrow.javedan@moffitt.org

Abstract

The present work investigated the potential of compensator-based intensity-modulated radiation therapy (CB-IMRT) as an alternative to multileaf collimator (MLC)-based intensity-modulated radiation therapy (IMRT) to treat malignant pleural mesothelioma (MPM) post extrapleural pneumonectomy. Treatment plans for 4 right-sided and 1 left-sided MPM post-surgery cases were generated using a commercial treatment planning system, XIO/CMS (Computerized Medical Systems, St. Louis, MO). We used a 7-gantry-angle arrangement with 6 MV beams to generate these plans. The maximum required field size was 30 x 40 cm. We evaluated IMRT plans with brass compensators (.Decimal, Sanford, FL) by examining isodose distributions, dose-volume histograms, metrics to quantify conformal plan quality, and homogeneity. Quality assurance was performed for one of the compensator plans. Conformal dose distributions were achieved with CB-IMRT for all 5 cases, the average planning target volume (PTV) coverage being 95.1% of the PTV volume receiving the full prescription dose. The average lung V20 (volume of lung receiving 20 Gy) was 1.8%, the mean lung dose was 6.7 Gy, and the average contralateral kidney V15 was 0.6%. The average liver dose V30 was 34.0% for the right-sided cases and 10% for the left-sided case. The average monitor units (MUs) per fraction were 980 MUs for the 45-Gy prescriptions (mean: 50 Gy) and 1083 MUs for the 50-Gy prescriptions (mean: 54 Gy). Post surgery, CB-IMRT for MPM is a feasible IMRT technique for treatment with a single isocenter. Compensator plans achieved dose objectives and were safely delivered on a Siemens Oncor machine (Siemens Medical Solutions, Malvern, PA). These plans showed acceptably conformal dose distributions as confirmed by multiple measurement techniques. Not all linear accelerators can deliver large-field MLC-based IMRT, but most can deliver a maximum conformal field of 40 x 40 cm. It is possible and reasonable to deliver IMRT with compensators for fields this size with most conventional linear accelerators.

Arrossi AV, Lin E, Rice D, Moran CA.

Department of Anatomic Pathology, University of Texas M.D. Anderson Cancer Center, Houston, USA.

Abstract

We studied 56 cases of malignant pleural mesothelioma (MPM) treated with extrapleural pneumonectomy (EPP). The slides from the EPP specimens were reviewed, and tumors were classified with the guidance of the World Health Organization classification of pleural tumors. Agreement between the histologic type from the EPP review and the diagnostic procedure (DP) reports was evaluated. Histologic and clinical parameters were also correlated with clinical outcome. There was a significant disagreement (P = .0001) between the histologic type in the DP reports and the EPP specimen review. The histologic type from the DP was associated with disease-specific survival (DSS); however, the histologic type from the EPP specimen was not associated with survival. Postoperative treatment was associated with DSS and with recurrence-free survival. Our study confirms that in many cases, final histopathologic typing of MPM is influenced by complete surgical resection and that initial biopsy should be carefully weighed in the treatment stratification.

Flores RM, Routledge T, Seshan VE, Dycoco J, Zakowski M, Hirth Y, Rusch VW.

Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. floresr@mskcc.org

Abstract

Objectives: The propensity of malignant pleural mesothelioma to metastasize to N1 or N2 nodes and their corresponding prognostic value is unclear. The American Joint Committee on Cancer staging system groups N1 and N2 disease together as stage III. The goal of this study was to define the prognostic value of specific nodal stations.

Methods: Patients with malignant pleural mesothelioma who underwent resection were identified from an institutional database. Nodal stations were defined by the American Joint Committee on Cancer lung cancer node map classification. Survival was analyzed by the Kaplan–Meier method, log-rank test, and Cox proportional hazards analysis.

Results: From 1990 to 2006, 348 patients were identified: 279 men and 69 women with a median age of 67 years (range 26–85 years). Extrapleural pneumonectomy was performed in 223 cases, and pleurectomy/decortication was performed in 125 cases. Survival differences (P < .01) were observed between 2 groups: N0 or N1(+) (median survival = 19 months) and N2(+), N2/N1(+) and internal thoracic(+) (median survival = 10 months). Survival was influenced by the number of involved N2 stations (0, 1, 2, or more: P < .001). Multivariate analysis grouping all N2 and internal thoracic(+) versus N1(+) and N0 demonstrated a hazard ratio for survival of 1.7 (P < .0001) controlling for T3/T4 status (hazard ratio = 1.3, P < .01), non-epithelioid histology (hazard ratio = 1.7, P < .0001), extrapleural pneumonectomy (1.1, P = .4), and male gender (hazard ratio 1.4, P < .01).

Conclusion: This study confirms a preferential pattern of drainage of malignant pleural mesothelioma to N2 rather than N1 lymph nodes, but suggests that N1 only nodal involvement should be classified as lower stage disease. Multiple N2 nodal site involvement could potentially be classified as higher stage disease than single station N2. Our results emphasize the need for larger, confirmatory multicenter studies that could lead to revision of the current staging system.

Sørensen JB, Ravn J, Loft A, Brenøe J, Berthelsen AK; Nordic Mesothelioma Group.

Aaseboe U, Billing B, Bjørck T, Brodin O, Brunsvig P, Forsløw U, Frank H, Hansen O, Harving H, Hillerdal G, Jakobsen KD, Johansson A, Ladegaard L, Lindh B, Melgaard P, Mygind N, Månsson T, Palshof T, Sundstrøm S, Sørensen P, Vigander T.

Department of Oncology, Finsen Centre/National University Hospital, Copenhagen, Denmark. jens.benn.soerensen@rh.regionh.dk

Abstract

Objectives: Extrapleural pneumonectomy (EPP) in MPM may be confined with both morbidity and mortality and careful preoperative staging identifying resectable patients is important. Staging is difficult and the accuracy of preoperative CT scan, 18F-FDG PET/CT scan (PET/CT), and mediastinoscopy is unclear. The objectives were to compare these staging techniques to each other and to surgical–pathological findings.

Methods: Patients had epithelial subtype MPM, age ≤70 years, and lung function test allowing pneumonectomy. Preoperative staging after 3–6 courses of induction chemotherapy included conventional CT scan, PET/CT, and mediastinoscopy. Surgical–pathological findings were compared to preoperative findings.

Results: Forty-two consecutive patients were without T4 or M on CT scan. PET/CT showed inoperability in 12 patients (29%) due to T4 (7 patients) and M1 (7 patients). Among 30 patients with subsequent mediastinoscopy, including 10 with N2/N3 on PET/CT, N2 were histologically verified
in 6 (20%). Among 24 resected patients, T4 occurred in 2 patients (8%), and N2 in 4 (17%), all being PET/CT negative. PET/CT accuracy of T4 and N2/N3 compared to combined histological results of mediastinoscopy and EPP showed sensitivity, specificity, positive predictive value, negative predictive value, and positive and negative likelihood ratios of 78% and 50%, 100% and 75%, 100% and 50%, 94% and 75%, not applicable and 5.0, and 0.22 and 0.67, respectively.

Conclusions: Non-curative surgery is avoided in 29% out of 42 MPM patients by preoperative PET/CT and in further 14% by mediastinoscopy. Even though both procedures are valuable, there are false negative findings with both, urging for even more accurate staging procedures.

Keywords: Mesothelioma; Staging; PET/CT scan; Mediastinoscopy; Extrapleural pneumonectomy

Ramalingam SS, Belani CP.

Emory University School of Medicine, Winship Cancer Institute, Atlanta, Georgia, USA.

Abstract

Malignant pleural mesothelioma clinically manifests after decades of initial exposure to etiologic agents, such as asbestos, and presents with nonspecific symptoms such as dyspnea, pain, or weight loss. In patients with limited, resectable disease, surgical therapy with extrapleural pneumonectomy or pleurectomy is recommended, although, it is unclear which approach is superior. Radiation has a limited role and is used primarily for palliation. The palliative efficacy of traditional chemotherapeutic agents and combination regimens is modest at best. The combination of cisplatin and pemetrexed, a novel multitargeted antifolate agent, is the approved "standard of care" for patients with unresectable malignant pleural mesothelioma. A number of molecularly targeted agents are currently under evaluation for mesothelioma such as the Histone deacetylase (HDAC) inhibitors that have demonstrated promising anticancer activity. Vorinostat, a small molecule inhibitor of HDAC, which targets select members of class I and II HDACs, has shown early evidence of activity and is currently being evaluated in a randomized study for patients who progress with standard therapy for advanced mesothelioma. It is hoped that the HDAC inhibitors and other novel targeted agents will pave the way for improved outcomes for patients with this disease.

Kent M, Rice D, Flores R.

Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Abstract

Opinion statement: The clinical presentation of malignant pleural mesothelioma (MPM) is nonspecific. The process to obtain the correct diagnosis can be challenging and requires a high index of suspicion. Once the diagnosis is made, there is no universally accepted standard of care and treatment decisions are strongly influenced by physician bias. Physicians who see few numbers of patients tend to treat based on symptoms alone by drainage of the pleural effusion and talc pleurodesis, while physicians at several tertiary referral centers tend to take an aggressive multimodality approach incorporating surgical resection, chemotherapy, and radiation. The primary goal of surgery in this setting is the resection of all gross disease. The choice of operation, extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D), depends on disease stage, pulmonary function, philosophy of the treating physician, and type of planned adjuvant therapy.