The Proposed New International TNM Staging System for Malignant Pleural Mesothelioma: Application to Imaging

Transcription

1 :. #{149} :. #{149}..: #{149}. #{149}. :- : Received June 22, 1995; accepted after revision September 12, Department of Radiology, Duke University Medical Center, Box 3808, Dunham, NC Address correspondence to E. F. Patz, Jr. 2Division of Thonacic Surgery, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY AJR 1996;166: X/96/ American Roentgen Ray Society Perspective The Proposed New International TNM Staging System for Malignant Pleural Mesothelioma: Application to Imaging Edward F. Patz, 1, Valerie W. Rusch2, Robert Heelan3 Malignant pleural mesothelioma (MPM) Is an uncommon and usually fatal primary neoplasm of the pleura. In the past, response to standard therapy has been poor [1-3], but recent studies suggest that some patients may benefit from various therapeutic options, including surgical resection, combined technique treatment, and Immunotherapy [4-i]. With improvements in therapy, an accurate, widely accepted staging system will be important in selecting homogeneous groups of patients for entry into clinical trials. Multiple staging systems have previously been proposed for MPM, but none are universally used (8]. To address this problem, members of the International Mesothelioma Interest Group, a multidisciplinary group of thoracic surgeons, radiation and medical oncologists, pathologists, and radiologists, met in June 1994 during the fourth International Association for the Study of Lung Cancer Conference to develop a new staging system. The purpose of the workshop was to develop a consensus on clinical, radiographic, and pathologic staging that would be internationally accepted for clinical trials. The proposed new International Mesothelioma Interest Group staging system is a TNM system, derived from recent data suggesting that overall survival in MPM is related to the extent of the primary tumor (T status) and to lymph node involvement (N status) [4, 9, 10]. Although the ability of CT and MR imaging to stage MPM accurately in this new system is under investigation, the objective of this manuscript is to emphasize how the new staging system may be applied to radiographic evaluation. NewTNM Staging System The rationale for the proposed new staging criteria for MPM has been described previously [1 1], and an outline of the system is shown in Tables 1-3. It includes precise TNM descriptors, which are grouped into four stages. These TNM descriptors are primarily based on surgical and pathologic findings but are also potentially applicable to radiographic staging by CT and MR imaging. Tia describes an early tumor that involves only the ipsilateral parietal pleura with or without tumor on the diaphragmatic or mediastinal pleura. Tib describes a slightly more advanced tumor that involves all pleural surfaces, including the visceral pleura. Patients with Ti disease usually have a free pleural space and present with a large pleural effusion (Fig. 1). T2 designates a tumor that cannot be fully removed without resecting the underlying lung (Figs. 2A and 2B). Usually, the diaphragmatic muscle is also involved. Patients with T2 disease may still have a free pleural space with an effusion, but the panetal and visceral pleural surfaces have often begun to fuse. As such, the pleural effusion may have resolved or be loculated. T3 describes a locally advanced tumor that is still potentially amenable to surgical resection of all gross disease. In addition to involvement of all the pleural surfaces, there may be areas of tumor extension into the endothoracic fascia or the mediastinal fat. The surface of the pericardium may be involved such that partial pericardiectomy rather than just removal of the

2 324 PATZ ET AL. AJR:166, February 1996 TABLE 1 : T Descriptor Status Region Involved Characteristics Tia Limited to ipsilateral panietal pleura, including No involvement of visceral pleura mediastinal and diaphragmatic pleura Tlb Ipsilateral panietal pleura, including mediastinal and Scattered foci of tumor also involving visceral pleura diaphnagmatic pleura T2 Each ipsilateral pleural sunfacea At least one of the following:. Involvement of diaphragmatic muscle SConfluent visceral pleural tumor (including fissures) or extension of tumor from visceral pleura into underlying pulmonary parenchyma T3 Locally advanced but potentially resectable tumor; each ipsilatenal pleural sunfacea T4 Locally advanced technically unresectable tumor; each ipsilateral pleural sunfacea a Panietal, mediastinal, diaphnagmatic, and visceral pleura. TABLE 2: N and M Designations Designation Description NX Regional lymph nodes not assessable NO No regional lymph node metastases Ni Metastases in ipsilatenal bronchopulmonary or hilar lymph nodes N2 Metastases in subcannal or ipsilateral mediastinal lymph nodes, including ipsilateral internal mammary nodes N3 Metastases in contralateral mediastinal, contralatenal internal mammary, and ipsilateral on contralateral supraclavicular lymph nodes MX Distant metastases not assessable MO No distant metastases Ml Distant metastases present TABLE 3: Stages Stage Status Lymph Node Metastases Ia Tia NO MO lb Tib NO MO II T2 NO MO Ill AnyT3 AnyNl orn2 MO IV AnyT4 AnyN3 Any Ml mediastinal pleura overlying the pericardium is required (Figs. 3A-3C). A solitary, completely resectable focus of tumor At least one of the following: #{149} Involvement of endothoracic fascia #{149} Extension into mediastinal fat #{149} Solitary, completely resectable focus of tumor extending into soft tissues of chest wall #{149} Nontransmural involvement of penicardium At least one of the following: #{149} Diffuse extension or multifocal masses of tumor in chest wall, with or without associated rib destruction #{149} Direct transdiaphnagmatic extension of tumor to pentoneum #{149} Direct extension of tumor to contralateral pleura #{149} Direct extension of tumor to one or more mediastinal organs #{149} Direct extension of tumor into spine #{149} Tumor extending through to internal surface of penicardium with on without pericardial effusion, or tumor involving myocardium extending directly into the chest wall is also included in the T3 category. This focus usually occurs in patients who have a tumor implant in the chest wall at the site of a previous diagnostic thoracentesis, pleural biopsy, or thoracoscopy. It is also occasionally seen in patients who present with a dominant parietal pleural mass. Although no data indicate that a specific size limitation should be placed on the area of chest wall involvement, the concept of focal direct extension of tumor is similar to that used in the T3 category of the lung cancer staging system. This is surgically quite distinct from a very locally advanced tumor that is technically unresectable because it diffusely invades the intercostal or chest wall muscles. T4 designates a locally advanced and technically unresectable tumor. In addition to involvement of all the pleural surfaces, T4 is characterized by features including diffuse extension of tumor into the chest wall, direct extension through the diaphragm to the underlying peritoneum, or direct extension to the contralateral pleura, the mediastinal organs, the spine, the myocardium, or the internal surface ofthe pericardium (Fig. 4). The descriptors for the N status are identical to those used in the International Lung Cancer Staging System [12]. Ni describes involvement of the ipsilateral bronchopulmonary and hilar lymph nodes, and N2 describes involvement ofthe subcarinal or ipsilateral mediastinal lymph nodes and the ipsilateral internal mammary nodes. N3 designates metastases in the contralateral mediastinal, contralateral internal mammary, or ipsilateral or contralateral supraclavicular lymph nodes. The descriptors for M status are identical to those used for all other solid tumors. MO designates no evidence of metastatic disease, whereas Mi describes the presence of metastases outside the ipsilateral hemithorax (Fig. 5).

3 AJR:166, February 1996 NEW STAGING FOR MESOTHELIOMA 325 Fig. 1.-Diffuse right-sided pleural disease in 69-year-old woman with resectable malignant pleural mesotheiioma. T2-weighted cardiac gated image (10-mm slice thickness) at level of left atrium shows large amount of fluid with only minimal soft-tissue component. In major fissure there is soft-tissue density, somewhat ovoid, corresponding to tumor involving visceral pleura (arrow). Radlologically, this wasti tumor and was confirmed at surgery to be Ti b. Fig. 2.-Encasement of right hemithorax in 75-year-old man with resectable malignant pleural mesothelioma. A, CT image at level of pulmonary artery demonstrates right pleural effusion posteriorly and bulky tumor anteriorly. Tumor appears to extend into anterior mediastinum and thus was radiologically T3 lesion (arrow). At thoracotomy, however, there was no mediastinal invasion, but invagination of mediastinal fat by tumor. Pathologically, lesion was thus T2. B, CoronalTl -weighted (5-mm slice thickness) cardiac gated view of anterior thorax shows bulky tumor compressing mediastinal structures. Smooth borders (arrow) suggest possibility of extrinsic pressure or Invaginatlon rather than true Invasion (T2 lesion). This tumor was completely resected at thoracotomy. Fig. 3.-Scattered focal soft-tissue pleural abnormality in 53-year-old woman with resectable malignant pleural mesothelioma. A, High-resolution CT scan (1.5-mm slice thickness) at level below carina shows extension of tumor beyond endothoracic fascia to involve intercostal regions in anterior chest wall (arrow). Thus, lesion was T3. Focal chest wall invasion was confirmed at surgery. In mediastinum, there is soft-tissue fullness to right of esophagus, suggesting enlarged mediastinal lymph node (N2 disease) (arrowhead). At thoracotomy, this proved to be an enlarged hyperplastic lymph node in the subcarinal region, which did not contain tumor (NO disease). B, T2-weighted cardiac gated (10-mm slice thickness) axial scan at level of aortlc valve plane also shows tumor within chest wall anteriorly (black arrow). In addition, tumor is seen in major fissure, involving visceral pleura (white arrow), and along mediastinal surface adjacent to heart (curved arrow). Pleural effusion is present in posterior pleural space. C, High-resolutIon (1.5-mm slice thickness) CT scan through lower chest shows subtle mass (arrow) adjacent to or involving pericardium. At surgery, full thickness of pericardium was involved by mesothelioma in this region (T3 lesion). Tumor is also present in major fissure. These TNM descriptors are used to characterize four stages of disease. Stages I and II include only node-negative tumors. Stage I is subdivided into Ia and lb on the basis of the difference in T status between Tia and Tib. Stage II includes only T2NO tumors. Stage III includes any T3, any Ni, or any N2, MO tumors. Stage IV includes any T4, N3, or Ml tumors. Discussion Until recently, little effort was made to stage MPM because it was a rare malignancy for which there was no effective treatment. However, the increasing occurrence of MPM makes it necessary to have a staging system that will stratify patients into homogeneous prognostic groups to evaluate new treat-

4 326 PATZ ET AL. AJR:166, February 1996 ment options in prospective clinical trials [13]. The staging system should be applicable to radiographic as well as to surgical and pathologic staging so that patients can be selected accurately for either surgical resection or nonsurgical therapy. The importance of having an accurate staging system and of identifying prognostic factors is well accepted in the study and treatment of other solid tumors and has facilitated selection of patients for novel treatment strategies. To improve the currently poor prognosis of MPM, systematic staging and classification of patients should be used in prospective multiinstitutional clinical trials. At least five staging systems for MPM have been proposed previously [8]. The staging system presented here defines specific TNM descriptors on the basis of emerging information about the natural history of MPM. This new staging system separates out subsets of patients with early, surgically resectable tumors. Previously, these categories were grouped together. The rising frequency of MPM and the increasing use of thoracoscopy for its early diagnosis as well as the apparently better prognosis of these tumor subsets justifies this stage grouping. Radiologic assessment of these tumors is integral to patient management, although surgical confirmation is often necessary. It appears that CT and MR imaging cannot always distinguish among Ti a, Ti b, and T2 because these techniques cannot usually differentiate parietal from visceral involvement or consistently detect diaphragmatic muscle invasion. However, in these early stages CT and MR imaging can evaluate the presence of a significant pleural effusion (Ti disease) and usually can differentiate it from extension of tumor through the visceral pleural to involve underlying lung parenchyma (T2 disease) [14]. Among patients with more locally advanced tumors, the distinction between T3 and T4 has obvious implications for surgical resection and apparently significant differences in survival. CT and MR imaging may have an impact in distinguishing T3 (potentially resectable MPM) from T4 (technically unresectable MPM) disease: these techniques can frequently aid in the diagnosis of several T3 categories (e.g., extension into mediastinal fat, solitary resectable chest wall tumor focus). Diagnosis by CT and MR imaging of involvement of the endothoracic fascia is considerably more difficult, representing anatomic distinctions at the limits of current imaging Fig. 4.-Diffuse tumor encasement of the right hemithorax in 73-year-old man with unresectable malignant pleural mesothelioma. CT scan through lower thorax shows thin soft-tissue rind (-5 mm) anteriorly and moderate pleural effusion. Within lateral chest wall fat, tissue infiltration increases subtly beyond the endothoracic fascia (arrows). At surgery, extensive tumor infiltration into chest wall was noted, precluding resection.this wast4 tumor. Fig. 5.-Metastatic disease in 74-year-old man with unresectable malignant pleural mesothelioma (MPM). CT image shows multiple small pulmonary nodules in right lung, pathologically proven to represent metastatic (Ml) MPM. capabilities. Similarly, involvement of the pericardium can be difficult to ascertain if there is anything less than extension through the entire thickness of the pericardium with effusion [i 5, 16]. Experience with detecting transdiaphragmatic extension of tumor to the peritoneum is limited. The coronal and sagittal capabilities of MR imaging may prove advantageous in this specific area [17, 18]. In imaging, the tendency is to understage the true extent of MPM, that is, to miss significant disease [15]. Understaging may be less important in the resectable stages (Ti-T3) but assumes greater importance in the diagnosis of T4 (unresectable) disease. At present, a percentage of patients in whom Ti-T3 disease is diagnosed by imaging may be presumed to have unresectable T4 disease at surgical exploration. The frequency of nodal involvement and its prognostic implications have only recently been investigated. The anatomic distinction between Ni, N2, and N3 nodes is familiar to all physicians caring for patients with thoracic neoplasms. Littie information is available about diagnosis by CT and MR imaging of nodal (Ni-N3) involvement in MPM. Preliminary experience in patients undergoing both resection of MPM and extensive mediastinal node sampling from a prospective study being performed by two of the authors found six of i 2 patients to have grossly suspicious nodes at surgery but no significant adenopathy on imaging studies. Two of the patients had histologically negative, hyperplastic nodes on pathologic examination; the rest were aggregates of lymph nodes, containing a total of 31 nodes, of which 1 i were positive for MPM. The largest single node was i.6 cm in diameter, and the vast majority were within normal size limits. Therefore, two factors may render imaging diagnosis of N disease difficult: involved nodes may not be enlarged, and large portions of the ipsilateral hilum and mediastinum may be obscured by bulky sheets of locally invasive or adjacent tumor. Systematic imaging searches for distant spread of MPM are not common when systemic symptomatology is absent and when the primary tumor appears to be at an early stage. Consequently, little imaging information is available about Mi spread of MPM. Although radiologic staging with CT or MR imaging provides a tremendous amount of information, surgical staging in

5 AJR:166, February 1996 NEW STAGING FOR MESOTHELIOMA 327 patients with potentially resectable lesions is often required [16]. In many respects, these discrepancies are similar to those seen in the radiographic staging of lung cancer. Were CT or MR imaging coupled with thoracoscopy, mediastinoscopy, and, when indicated, biopsies of other sites, it is likely that this staging system could stratify patients in clinical trials that do not include thoracotomy and surgical resection. No TNM staging system fully recognizes the pathologic and biologic variables that influence survival. Many factors are reported to be prognostic in MPM, including histology, age, sex, performance status, type of symptoms, weight loss, history of asbestos exposure, and platelet count [1, 10, 19-22]. Of these, only histology appears to be universal across all reported series. Epithelial histology is always associated with a significantly better outcome than other cell types. Although the TNM staging system presented here can accurately describe the anatomic extent of disease, clinical trials will also need to stratify tumors by histology for the purposes of survival analyses. Our understanding of MPM continues to evolve as we learn more about the biology and treatment of this disease. Despite limitations in the accuracy of CT and MR imaging, the new International Mesothelioma Interest Group staging system can be applied to the radiographic staging of MPM and will provide the framework for the prospective clinical studies that may alter the currently poor prognosis of MPM. ACKNOWLEDGMENT We thank Melody Owens for her expert assistance in the preparation of this manuscript. REFERENCES 1. Ruftie R, Feld R, Minkin 5, et al. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J C/in Oncol 1989;7: Knanup-Hansen A, Hansen HH. Chemotherapy in malignant mesothelioma: a review. Cancer Chemother Pharmacol 1991:28: Alberts AS, Falkson G, Goedhals L, Vorobiof DA, Van Den Merwe CA. Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers. J C/in Oncol 1988;6: Sugarbaker DJ, Heher EC, Lee TH, et al. Extrapleural pneumonectomy, chemotherapy, and radiotherapy in the treatment of diffuse malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1991:102: Pass HI. Contemporary approaches in the investigation and treatment of malignant pleural mesothelioma. ChestSurg Clin NAm 1994:4: Boutin C, Viallat J-R, Van Zandwijk N, et al. Activity of intrapleural recombinant gamma-interferon in malignant mesothelioma. Cancer : Buchart EG, Gibbs AR. Pleural mesothelioma. Curr Opin Oncol 1990:2: Dimitrov NV, McMahon S. Presentation, diagnostic methods, staging, and natural history of malignant mesothelioma. In: Antman K, Aisner J, eds. Asbestos-related malignancy. Orlando: Grune & Stratton, 1987: Sugarbaker DJ, Strauss GM, Lynch TJ, et al. Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J C/inOncol 1993:11: Tammilehto L, Kivisaani L, Salminen US, Maasilta P, Mattson K. Evaluation of the clinical TNM staging system for malignant pleural mesothelioma: an assessment in 88 patients. Lung Cancer 1995:12: Rusch VW, the International Mesothelioma Interest Group. A proposed new international TNM staging system for malignant pleural mesothelioma. Chest 1995;108: Mountain CF. A new international staging system for lung cancer. Chest 1986;89(suppl): Osteen AT. Cancer manual, 8th ed. Boston: American Cancer Society, 1990: Kawashima A, Libshitz HI. Malignant pleural mesothelioma: CT manifestations in 50 cases. AJR 1990:155: Ausch VW, Godwin JD, Shuman WR The role of computed tomography scanning in the initial assessment and the follow-up of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1988:96: Law MA, Gregor A, Husband JE, Kerr H. Computed tomography in the assessment of malignant mesothelioma of the pleura. Clin Radiol 1982:33: Patz EF, Shatter K, Piwnicka-Worms DR, et al. Malignant pleural mesothelioma: value of CT and MA imaging in predicting resectability. AJR 1992:159: Lonigan JG, Libshitz HI. MA imaging of malignant pleural mesothelioma. J Comput Assist Tomogrl989;13: Tammilehto L. Malignant mesothelioma: prognostic factors in a prospective study of 98 patients. Lung Cancer 1992:8: Rusch VW, Piantadosi S, Holmes EC. The role of extrapleural pneumonectomy in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1991;102: Spirtas A, Connelly AR, Tucker MA. Survival patterns for malignant mesothelioma: the SEER experience. lntj Cancer 1988:41: Antman KH, Shemin A, Ryan L, et al. Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana-Farber Cancer Institute and Brigham and Women s Hospital experience over two decades, J C/in Onco/1988;6: