Several non-anatomical features of NSCLC, such as EGFR/KRAS mutation[9], Spread Through Air Space (STAS)[11, 12], mitotic counts[13], genomic profile[14] have a strong influence on prognosis, but, to date, they are not considered in the TNM staging system.
In our study we analyzed the presence of high-grade patterns, namely micropapillary and solid as prognostic factor, and its impact on possible postoperative management. High-grade components are well-known and already established negative prognostic factors by several authors [2–5, 15–17]. Sica and colleagues[18], firstly highlighted that in metastatic lung adenocarcinoma with a non-predominant micropapillary or solid pattern, high-grade patterns were instead predominant in the metastasis tissue. Recently, a multi-institutional European group[5] explored the impact of second predominant pattern on DFS finding that the only influence was given by the presence of either micropapillary or solid pattern in the tumor. Concurrently, Yoshizawa and coworkers[4, 10], in two different papers, highlighted the significant prognostic impact of IASLC/ATS/ERS classification, concluding that it should have been included in the T descriptors. Similarly, Ito and colleagues[19] analyzed T1a and T1b lung adenocarcinoma finding that those with a smaller invasive component (namely adenocarcinoma in situ, AIS, and minimally invasive adenocarcinoma, MIA) had a significantly better DFS compared to invasive T1 adenocarcinoma. In this study we aimed to assess whether the very presence of a high-grade pattern could be considered an independent prognostic factor for OS or DFS. Our data showed that outcomes of T1a-b-cN0 lung adenocarcinomas with a high-grade component were more similar to T2a rather than T1a-b-c without high-grade components. Conversely, no further differences were seen comparing T component according to the presence of a high-grade subtype, suggesting that the tumor dimensions define its aggressivity. We hypothesize that in T1 tumors the presence of a high-grade pattern could cause a difference in survival, like visceral pleura invasion (PL1 or PL2). To the best of our knowledge, this is the first study reporting significant differences in survival rates between tumors with the same T component but different grade histological subtypes.
These results might have important clinical implications: a risk stratification based on the presence of a high-grade pattern, might allow a more accurate perioperative management. As a matter of fact, to date, NCCN guidelines[7] recommend adjuvant therapy in case of stage IB NSCLC (T2aN0) with particular risk factors, such as poorly differentiated tumors, vascular invasion, wedge resection, visceral pleural involvement, and incomplete lymph node sampling. Consistently, Yoshiya[20] suggested a possible benefit of adjuvant therapy in case of micropapillary or solid patterns of small-sized (< 2 cm) lung adenocarcinoma considering the presence of these high-grade patterns as a risk factor for a worse OS and DFS; the same conclusions were shared by Zhang[21]. On the other hand, high-grade patterns generally showed a good response to chemotherapy, even though results on OS and DFI were inconsistent. In a large series of patients taken from previous clinical trials, Tsao[22] reported a significant impact of adjuvant treatments on DFS, but not on OS; similar conclusions were drawn by Luo and coworkers[23] in a subset of high-grade predominant pattern stage IB adenocarcinomas. Lastly, investigating the prognostic role of adenocarcinoma subtypes in stage IB patients, Ma[24] reported a significantly better DFS of adjuvant chemotherapy only in patients with high-grade predominant pattern. Conversely, Whang and colleagues[25] found a significant impact both on OS and DFS in a group of stage IA micropapillary adenocarcinomas. In our study, since only 20 patients (3.3% of our cohort) underwent adjuvant chemotherapy, we did not perform any analysis on its impact on OS or DFS as no significant conclusions would have been robust enough. Nevertheless, we might speculate that a preoperative diagnosis of high-grade pattern could at least influence the surgeons’ choice preferring a larger and more radical resection, such as a lobectomy, rather than sublobar resections.
Recently, sublobar resections were proposed as standard of care in tumors smaller than 2 cm, while for bigger tumors lobectomy or multi-segmental resections are still the standard of care[26, 27]. Similarly, the presence of Spread Through Air Space (STAS), which is more frequent in high-grade adenocarcinomas, has been verified to be a risk factor for early recurrence and worse survival in case of limited resections compared to lobectomy[28]. Although our series was not intended to verify differences according to the extent of the resection, we investigated possible differences in outcomes. No differences in OS and DFS were seen neither in the whole cohort nor in the subgroup of high-grade component according to a lobar or sublobar resection; moreover, lobectomy compared to other resections was not a significant prognostic factors in univariable and multivariable analysis.
Although the present study was based on a large multi-institutional database, it presents some limitations that might have influenced the quality of data and eventually the results. The major limitations are the retrospective character of the study; the missing data (e.g.: in 29% of cases data on lymphovascular invasion were missing; data on mutational status and targeted therapies were not available for most patients) and the absence of an external review or concordance analysis regarding the analysis of pathological specimens at each independent institution.
In conclusion, micropapillary and solid patterns confirm their detrimental effect on OS and DFS. The results of our study suggest that patients affected by a T1a-b-c adenocarcinoma with a high-grade pattern have similar survival outcomes of pT2a tumors. On the other hand, the effect of high-grade pattern on larger tumors seems to be marginal. According to these data, we believe that patients affected by T1a-b-c lung adenocarcinoma with a high-grade histological component should be considered for a more careful perioperative management encompassing anatomical resections and possible adjuvant therapy and/or closer surveillance.
Prospective larger studies are needed to validate these findings and properly evaluate benefit of postoperative treatment or different surveillance management in these patients.