First described in 2015, tumor spread through air spaces is a recently recognized form of invasion in lung carcinoma, but it has not been well described in lung squamous cell carcinoma. However, a study out of Memorial Sloan-Kettering Cancer Center reports spread through air spaces (STAS) is one of the most significant histologic findings in lung squamous cell carcinoma (SCC).

In multivariable models for any recurrence and lung cancer–specific death, the researchers found that STAS was a significant independent predictor for both outcomes (P = .034 and .016, respectively).

“We found that STAS in lung SCC was associated with p-stage, lymphatic and vascular invasion, necrosis, larger nuclear diameter, increased mitoses and high Ki-67 labeling index,” wrote lead author Shaohua Lu, MD, and coauthors ( J Thorac Oncol. 2017 Feb;12[2]:223-34 ). Their findings are based on an analysis of 445 patients who had resection for stage I-III SCC over a 10-year period ending in 2009.

The Sloan-Kettering Group previously reported that STAS was a predictor of recurrence in stage I lung adenocarcinoma patients who had a limited resection ( J Thorac Oncol. 2015;10[5]:806-14 ), and others reported STAS was a clinically significant finding in the disease. In the latest study, Dr. Lu and colleagues set out to determine if STAS is associated with tumor aggressiveness in lung SCC by using a large cohort of patients who had lung SCC resection. The lung resections they studied are from the aforementioned 2015 study that used immunohistochemistry to confirm squamous differentiation in otherwise poorly differentiated tumors.

Two pathologists reviewed tumor slides and used Ki-67 staining to confirm squamous differentiation. The study population comprised 98% former smokers and the median age was 71.3; 76% (336) were older than 65.

Dr. Lu and colleagues noted how STAS in lung SCC differs from its presentation in lung adenocarcinoma. “In contrast to lung adenocarcinoma, in which STAS can manifest as micropapillary clusters, solid nests or single cells, all STAS lesions in lung SCCs consist of solid tumor cell nests,” they wrote.

They found that STAS was associated with a higher risk of recurrence in SCC patients who had lobectomy, but not sublobar resection, whereas in patients with lung adenocarcinoma STAS was associated with a high risk of recurrence if they had sublobar resection.

The study observed STAS in 132 patients (30%). With a median follow-up of 3.4 years, 61% (273) of all patients died in that time. STAS tumors were more aggressive in nature than were non-STAS tumors. Pathologic features strongly associated with STAS were lymphatic invasion (40% for STAS vs. 19% for non-STAS patients); vascular invasion (36% vs. 22%); larger tumor size (median 4 cm vs. 3 cm); higher Ki-67 labeling index (32% vs. 13%); and higher tumor stage (23% with p-stage I, 35% p-stage II, and 43% p-stage III), all significant differences. Patients with STAS also had a higher 5-year cumulative incidence of any recurrence (39% vs. 26%) and lung cancer-specific death (30% vs. 14%), both significant differences.

STAS has an “insidious pattern of tumor invasion” that can be difficult for pathologists to detect and requires the gathering of specimens that include the adjacent lung parenchyma, Dr. Lu and colleagues said. They also dispelled the myth that STAS is an ex vivo artifact. “STAS is morphologically different from tissue floaters and contaminant or extraneous tissues that can lead to diagnostic errors,” they said.

And while the study showed that STAS is an independent predictor of recurrence and cancer-specific death, it was not predictive of overall survival – perhaps because most of the study population was over age 65 and were more likely to die from other causes rather than lung cancer. “We found a strong correlation between STAS and high-grade morphologic patterns such as nuclear size, nuclear atypia, mitotic count and Ki-67 labeling index, suggesting that STAS is associated with tumor proliferation,” Dr. Lu and coauthors said.

“Because we found STAS to show greater prognostic significance than lymphatic vascular, and visceral pleural invasion, all of which are histologic features recommended to be recorded in pathology reports for lung cancer specimens, in the future, STAS may be appropriate to add to this list,” the researchers noted.

Dr. Lu and coauthors had no financial relationships to disclose.


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