Histopathological features and prognostic significance of the micropapillary pattern in lung adenocarcinoma

Abstract

The micropapillary pattern is characterized by small papillary tufts with no fibrovascular core lying in spaces and has been reported as an aggressive variant of carcinoma in several organs. We investigated the histopathobiological properties of the micropapillary pattern with immunohistochemistry, serial sections, and electron microscopy in lung adenocarcinoma. We further analyzed its clinicopathological character and prognosis. The subjects included 383 adenocarcinoma cases, of which 184 (48%) were micropapillary patternpositive and 199 (52%) were micropapillary pattern-negative. On histology, micropapillary tufts seemed to float in the alveolar space or spaces encased by connective tissues, whereas serial sections revealed that most tufts had continuity with other tufts and even with the main tumor. Positive staining for the adhesion molecules E-cadherin and b-catenin suggested the preservation of tight adhesion, and electron microscopy showed the existence of intercellular junctions. Negative staining for laminin and loss of basement membrane as determined by electron microscopy suggest a loss of cell-matrix contact. Positive staining for Ki-67 indicates that cells constituting micropapillary tufts retained their proliferation potency. There were no CD34-positive cells in micropapillary tufts, and the loss of the vascular core was confirmed. In micropapillary pattern-positive cases, lymphatic invasion was identified significantly more frequently than in micropapillary pattern-negative cases (Po0.001), even at stageIA (without lymph node metastasis, N ¼ 197) (Po0.001). The 5-year and 10-year overall survival rates of the micropapillary pattern-positive stageIA group were 77.6 and 67.6%, respectively, which were significantly less than those of the micropapillary pattern-negative stageIA group (98.1 and 98.1%) (P ¼ 0.001). In conclusion, cells constituting the micropapillary pattern are likely to have acquired anchorage-independent growth and a potential for high malignancy.

Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas

“…The presence of a micropapillary pattern in lung adenocarcinomas reportedly correlates with increased propensity for metastasis, pleural invasion, and decreased survival among stage I patients. [22][23][24] Molecular analysis of the 41 lung adenocarcinomas with a micropapillary-predominant pattern in our study cohort revealed ALK rearrangements in 19 (46%) followed by KRAS mutations in 6 (15%) (data not shown), whereas others have demonstrated a strong association between EGFR mutations and the micropapillary pattern in previous studies with resection specimens. 25,26 These findings complement the evolving molecular characterization of micropapillary lung adenocarcinomas and support the recent recommendations by the IASLC/ATS/ERS to consider micropapillary architecture to be a distinct and potentially biologically significant histologic subtype.…”

“…As solid and micropapillary patterns of lung adenocarcinoma have been reported to have an increased propensity for metastasis, it is possible that any statistical predilection that ALK þ tumors show for a solid or micropapillary pattern is diminished by the overall higher prevalence of solid and micropapillary patterns at metastatic sites. 22,23,27 Although ALK þ primary lung adenocarcinomas were associated with the presence of hepatoid tumor cells and psammoma bodies, these associations also failed to be preserved in metastatic tumors. It is currently unclear why these morphologic features help distinguish ALK rearrangements in primary lung tumors but not in metastatic tumors.…”

Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases

“…28,29 The adverse prognosis associated with the micropapillary pattern, confirms observations in multiple previous studies and supports the addition of this new subtype to the classification. 10,11,[30][31][32][33] However, varied criteria for the diagnosis have been used with percentage of the micropapillary component including as little as 6% of the total tumor and none of these studies have utilized comprehensive histological subtyping to define this subgroup according to the predominant subtype showing comparison with survival of the other histological subtypes as we have done. 10,11,[30][31][32][33] Our finding that colloid adenocarcinomas also fit into this poor prognostic group was somewhat surprising as these tumors are often regarded as well-differentiated tumors, but this is the largest series of these tumors reported where survival analysis compared outcome with other adenocarcinoma histological types.…”

A Retrospective Study of Those Histopathologic Parameters Predictive of Invasion of the Lymphatic System by Canine Mammary Carcinomas

“…18,23,40,45 The aggressive behavior of the cells that produce micropapillae was attributed to their high proliferative activity, stimulation of angiogenesis, and anchorageindependent growth. 14,20 Vasculogenic mimicry was recently described in canine inflammatory mammary cancers and previously in several human malignant tumors, such as breast carcinomas, gliomas, melanomas, and hepatocellular carcinomas. 6,46 Human studies suggested that it furnishes an additional blood supply to the tumor and facilitates hematogenous dissemination.…”