269 General discussion and future perspectives adenocarcinomas due to the morphological adjustments in the revised classification. However, there is a clear requirement for additional independent studies on the matter. Collapsed AIS, and survival In chapter 13 we described a pilot study to examine the recognition of surgical collapsed AIS with a possible supportive role of CK7 and correlated this to prognosis320. This pilot study showed that cases reclassified as AIS based on a regular CK7 pattern and the presence of elastin fibers in pre-existing alveolar walls as aids to recognize collapsed AIS, did prevail a 100% recurrence free survival. Subsequently, this study was extended in chapter 14 and confirmed that cases diagnosed as (collapsed) AIS maintain the 100% recurrence free survival. The number of AIS cases in chapter 13 was 7 out of 40 tumors (17.5%), in the same range as the 10 out of 70 cases (14.3%) in chapter 14. An interesting aspect in the follow-up of lung cancer patients, and therefore also in patients diagnosed with AIS, is the development of a separate primary lung cancer (SPLC) or that of an intrapulmonary metastasis (IPM). The incidence in cases of AIS seems low. Yotsukura et al found in 5.6% of 207 AIS cases an SPLC in the followup315. Interestingly is the distinction from IPM’s, especially in invasive cases. Chang et al used comprehensive next-generation sequencing (NGS) to reliably separate one from the other385. In four cases with a 5-30% lepidic component, an IPM was also discovered, which came as a surprise. However, it’s worth noting that these cases were not predominantly lepidic. The argument put forth was that a lepidic component doesn’t necessarily indicate that the tumor began as an in situ lesion. Instead, the lepidic pattern could be the result of alveolar surface colonization by an invasive tumor that’s expanding. Similar cases have been reported where lung metastases from other organs, such as primary pancreas carcinoma, exhibit a lepidic growth pattern242. Even cases with lung metastasis of a malignant melanoma with a lepidic growth pattern have been reported386. Collapse and patient consequences The mathematical model presented here, can help to understand iatrogenic collapse and facilitate the diagnostic approach to collapsed AIS. In pulmonary adenocarcinomas this is essential in order not to overestimate AIS as invasive adenocarcinoma, as therapeutic consequences are obviously divergent. Moreover, the message towards the patient is essentially different: being cured of an in situ cancer or hoping for the absence of a recurrence in the future with an invasive carcinoma with inherent uncertain feelings. False negative diagnoses are the most clinically important category: they represent cases which go under-treated and might, if an area of invasive growth is missed, not receive possibly curative adjuvant therapy. Consequences of false negative cases are large for individual pathologists in the USA, as pathologists cannot afford the costs after being juridically sued for a missed diagnosis of malignancy. This explains a more defensive judgment of possible non-invasive cases and is a known phenomenon among 17
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