Aerogenous spread of primary lung adenocarcinoma induces ultrastructural remodeling of the alveolar capillary endothelium

To determine whether pulmonary alveolar capillaries manifest ultrastructura l remodeling at areas of neoplastic invasion of primary I ng adenocarcinoma s, we examined 17 well-differentiated adenocarcinomas of lung (2 bronchiolo alveolar and 15 papillary adenocarcinomas) by electron microscopy. The expr ession of vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) was demonstrated by immunohistochemical stainings. V EGF messenger RNA (mRNA) isoforms were detected by reverse-transcription po lymerase chain reaction (RT-PCR) in alveolar walls microdissected from norm al and tumor-associated tissues. Cytoplasm of neoplastic cells expressed VE GF protein in all patients. Endothelial cell nuclei of alveolar capillaries showed positive reaction for PCNA. Alveolar capillary lumina were distende d like venules, and some intercellular junctions remained open. The cytopla sm of the capillary endothelial cells was enlarged and developed numerous o rganelles such as Weibel-Palade bodies and vesiculovacuolar organelles, in contrast to marked attenuation in their normal counterpart. Capillary sprou ting occurred from proper alveolar capillaries in 2 patients. Cytoplasmic s egments became extremely attenuated and developed diaphragm-like fenestrae in 65% of the patients. A relatively higher expression of diffusable isofor ms of VEGF mRNA was seen in the tumor-bearing alveolar walls than in normal walls. Expression of KDR (one of the VEGF receptors) mRNA in tumor exceede d that in normal tissues. These results suggest that diffusable isoforms of VEGF mRNA released from the neoplastic cells are deeply involved in the in duction of growth activity of alveolar capillary endothelial cells as much as in the characterization of tumor-associated microvessels in primary lung adenocarcinomas. Hum PATHOL 32:1050-1058. Copyright (C) 2001 by W.B. Saund ers Company.