Objectives:
l Review various problems associated with the frozen section diagnosis of small pulmonary nodules
l Review problems associated with current guidelines for the pathologic staging of resected NSCLC
l Discuss the value of prognostic and predictive “markers” in patients with resected NSCLC
l Discuss the current WHO classification of Thymic Tumors
Review current guidelines for the reporting of thymomas

New imaging modalities are creating diagnostic challenges for pathologists. Lung nodules as small as 5 mm in diameter are frequently detected with high-resolution CT scan (HRCT), and spiral CT and studied with FDG-PET scan and PET-CT. These small lesions are difficult to biopsy with transthoracic FNA and transbronchial biopsies and are frequently first diagnosed by intraoperative consultation with frozen section (FS). It can be difficult to distinguish small adenocarcinomas (AC) of the lung and bronchioloalveolar carcinomas of the lung (BAC) from reactive epithelial atypical changes. However, as open lung biopsies using video-assisted thoracoscopic surgery (VATS) or thoracotomy have a certain morbidity, thoracic surgeons require a diagnosis based on FS, followed by lobectomy or other resection during the same operation. In a recent study from our laboratory, the sensitivity of FS diagnosis of lesions smaller than 1.1 cm was 80.5%, with 100% specificity. Larger lesions ranging in size from 1.1 cm to 1.5 cm were diagnosed with 100% sensitivity and 96.8% specificity. Various FS diagnostic problems included the distinction between AC and BAC from organizing pneumonia with atypia, lymphomas, granulomatous pneumonia with epithelial atypia, carcinoid tumors.

The College of American Pathologists has developed, through its cancer resource committee multiple protocols and checklists for the reporting of most common neoplasms, including lung cancer and thymoma. They are available for download in pdf or Microsoft Word format at www.cap.org. These guidelines are now required for the accreditation of multi-specialty Cancer Centers in the U.S. The CAP cancer protocols and checklists have been developed by groups of experts, without using an Evidence-based approach. Indeed, to my knowledge, there are no EBM guidelines in Pathology for either lung or mediastinal neoplasms. The CAP protocols and checklists include a list of “elements” that need to be included in a cancer report. The elements are classified as either required or optional, according to the decision of the group of experts that wrote the documents. The required elements for lung cancer reporting include the diagnosis, using the categories from the most recent WHO classification scheme and the features needed to provide a tumor stage, according to the 6th Edition of the American Joint Commission on Cancer Manual. Pathologists trying to use these documents are faced with certain ambiguity in some of the diagnostic criteria and in the definition of certain features, such as pleural invasion and nodal status.

The distinction between SCLC and other lung neoplasms is accurate in over 90% of cases, but it can be difficult to distinguish these neoplasms from other neuroendocrine neoplasms such as large cell neuroendocrine carcinoma and atypical carcinoid tumor, and from selected NSCLC such as squamous cell carcinoma, small cell variant, adenoid cystic carcinoma and other neoplasms. These diagnostic problems can be particularly difficult at the time of frozen section. A lung tumor of any size that either infiltrates the visceral pleura, is larger than 3.0 cm in dimension, or involves proximal to a lobar bronchus without extending within 2 cm of the carina and/or resulting in atelectasis of an entire lung is categorized as pT2. If regional lymph nodes are negative for metastatic carcinoma (pN0), patients with pT1 tumors are staged as Stage IA, while those with pT2 lesions are categorized as Stage IB. Patients with Stage IA NSCLC have about 10% better 5-year survival rates than patients with Stage IB disease. Recent clinical trials in Canada and the U.S. have suggested that patients with Stages IB and higher can benefit from post-operative adjuvant chemotherapy. Although adjuvant chemotherapy results in modest improvements in 5-year survival rates, in the order of 4.5% to 15%, oncologists are beginning to offer adjuvant chemotherapy routinely to patients with Stage IB and Stage II NSCLC. This recent practice underscores the need for pathologists to accurately distinguish pT1 from pT2 lung lesions. However, the current AJCC/UICC lung cancer staging guidelines do not specifically indicate whether peripheral neoplasms measuring less than 3 cm in dimension should be staged as pT2 only when the tumor infiltrates the entire visceral pleura into the pleural surface. It is unclear whether neoplasms that partially infiltrate the visceral pleura, should be staged as pT1 or pT2. Other details of AJCC staging, such as the use of keratin immunostains for the assessment of nodal status, evaluation of resection margins, and the distinction between pT1(m) and pT4 or pM1 will be discussed. Patients with two or more primary intrapulmonary neoplasms can be staged either as pT1(m) if both neoplasms are synchronous independent NSCLC, pT4 if the nodules are originating from the same neoplasm and are present within the same lobe or pM1 if they are nodules of the same neoplasm located in different lobes. Pleural tumor nodules involving either the visceral or the parietal pleura and located separate from the primary NSCLC are staged as pT4. These pleural lesions can be difficult to distinguish on frozen section from reactive mesothelial hyperplasia.

The second portion of the lecture will briefly discuss the current CAP guidelines for the reporting of patients with thymomas. The required elements in these reports include use of the WHO schema for “grouping” of thymomas and an assessment of Masaoka stage. The CAP thymoma protocol emphasizes the need for pathologists to thoroughly evaluate the capsular area of a thymoma, for possible transcapsular invasion and for the assessment of resection adequacy. Indeed, thymomas need to be assessed like a thyroid nodule with multiple sections of the capsule to evaluate for transcapsular invasion, while the more central portions of the tumor are less important for classification of the lesion as an encapsulated (Stage I), minimally invasive (Stage Ia) or frankly invasive thymoma (Stage Ib).

The WHO thymoma classification scheme is a compromise document that has attempted to bridge the differences between the schema proposed by Rosai and Levine, the use of the term “atypical thymoma” as proposed by Suster and Moran and the European classification developed by Muller-Hermelink and associates. In my view, the WHO grouping of thymic neoplasms into 3 categories A-B-C is simple but confusing, as it labels thymic carcinomas as “Thymoma C” and includes as Thymoma B3 cases that are considered by the European authors as “well-differentiated thymic carcinomas” and by Suster and Moran as presumably benign “atypical thymomas”. Yet, multiple studies with long-term follow-up have shown that some patients with neoplasms classified as any of these categories have developed recurrences or rare distant metastases. Multiple studies using the Masaoka staging system have reported excellent stratification of patients according to Stage. Completeness of excision and presence of residual disease (R1 or R2) have been shown to correlate with prognosis.

Most studies of thymic carcinomas have reported that these neoplasms have a considerably more aggressive clinical behavior and, in my opinion, the inclusion of these lesions in the WHO classification as “thymomas” lacks definitional clarity.

References :
1. World Health Organization Classification of Tumours: Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004.

2. Marchevsky A.M. Problems in Pathologic Staging of Lung Cancer. In Press, Arch Pathol and Lab Medicine, 2006.

3. Osaki T, Nagashima A, Yoshimatsu T, Yamada S, Yasumoto K. Visceral pleural involvement in nonsmall cell lung cancer: prognostic significance. Ann Thorac Surg 2004;77(5):1769-73.

4. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1975;70(4):606-12.

5. Marchevsky AM, Qiao JH, Krajisnik S, Mirocha JM, McKenna RJ. The prognostic significance of intranodal isolated tumor cells and micrometastases in patients with non-small cell carcinoma of the lung. J Thorac Cardiovasc Surg 2003;126(2):551-7.

6. Philipp Ströbel, Alexander Marx, Andreas Zettl, and Hans Konrad Müller-Hermelink. Thymoma and Thymic Carcinoma: An Update of the WHO Classification 2004. Surg Today (2005) 35:805–811.