Dear Dr. Safaa Mahmoud,
Thank you for your comments.
Your observation about the different forms of pleural involvement and their classification is almost exact, except for separate pleural nodules; they were T4, now M1a, the same as MPE.
On your first question, about the diagnosis and clinical staging of pleural effusions (PE) in patients with NSCLC, these are the rules for classification, word for word, according to the 6th edition of the TNM staging system (1-3):
“Most pleural effusions associated with lung cancer are due to tumor. However, there are a few patients in whom multiple cytopathologic examinations of pleural fluid are negative for tumor. In these cases, the fluid is non-bloody and is not an exudate. When these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be staged T1, T2, and T3.”
The opposite is also valid, that is to say, when the clinical picture is highly suggestive of MPE, despite a negative fluid cytology. We have to consider that pleural fluid cytology is diagnostic in only 60% of MPE (4, 5). There is evidence that clinical evaluation, including antecedent of cancer and CT characteristics, has a sensitivity of more than 90% in the diagnosis of MPE (6).
Clinical judgment is appropriate to establish the diagnosis of a MPE, when common diagnostic procedures had failed, in patients with microscopic confirmation of lung cancer, that due to the stage of the disease are not considered for treatment with curative intent (surgery with or without adjuvant therapy), and pathologic proof of MPE has no clinical relevance; consider that clinical stage guides initial management; pathologic stage defines prognosis.
If the diagnosis of cancer has not been established yet, or the patient has early stage disease, pathologic confirmation is mandatory. Most accepted approach for the diagnosis of exudative PE is:
• Cytological examination of pleural fluid; if negative repeat.
About 50% of MPE are negative at first thoracentesis (7).
• If second examination of pleural fluid is negative, do a contrast enhanced thoracic CT scanning to evaluate any pleural abnormality and make a decision to carry out a biopsy.
CT sensitivity for malignant pleural dissemination is about 85% (4, 8, 9).
• If thickening or nodularity is found, perform an imaging-guided pleural biopsy.
CT-guided pleural biopsy has almost 100% of sensitivity against 50% of blind biopsy (10, 11).
• If pleural biopsy is negative: do a thoracoscopy.
Your concern about the inconsistency in the statement that “diagnosis of a MPE can also be made by pleural biopsy, but in such cases disease is listed as M1 - stage IV” is absolutely justified. I appreciate very much your observation (and applaud your perspicaciousness). I didn’t notice the mistake; the correct statement must be that both, positive fluid cytology and pleural biopsy are valid to classify the tumor as T4 (according to the 6th edition). I am publishing an erratum right now.
On your commentary regarding the new pathology staging templates, I agree with you. Ideally every member of the multi-disciplinary team dedicated to the management of lung cancer should have the most complete and accurate information of the patient. In practice, communication between clinicians and pathologists is far from optimal.
The reason to exclude the M descriptor from the pathology staging templates is, as you mention, that pathologists usually do not have data about metastasis. The problem is that the pathologic assignment of the presence of metastases (pM1) requires a positive biopsy, consequently pMX does not exist. Pathologic classification of the absence of distant metastases (pM0) can only be made at autopsy. The risk of maintaining the M factor on the pathology staging templates is that if the pathologist does not know the clinical M he may consign a MX and exclude the case from staging.
Thank you again for your interest in the article.
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2. Sobin LH, Wittekind C eds. Lung and pleural tumours. In: Sobin LH, Wittekind C eds. UICC International Union Against Cancer, TNM classification of malignant tumours, 6th ed. New York: Wiley-Liss, 2002; pp. 97-107.
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