Frequent intra-regional PLAP expression heterogeneity in gastric adenocarcinomas

Placental alkaline phosphatase (PLAP), also known as alkaline phosphatase, placental type (ALPP) is a membranous protein which is thought to play a role in guiding migratory cells and transport specific molecules over the plasma membrane. In normal tissues, PLAP expression is almost exclusively seen in the placenta. In cancer, PLAP expression is a hallmark of testicular germ cell tumors but can also be found in up to 38% of gastric adenocarcinomas. The membranous location of PLAP in combination with the absence or only very low levels of PLAP expression in vital normal tissues of (non-pregnant) humans, makes PLAP a potentially useful therapeutic target. For targeted therapy, both the therapeutic success and the quality of the diagnostic assessment generally may critically depend on the degree of heterogeneity of target protein expression in a cancer. To study the extent of intratumoral heterogeneity of PLAP expression in gastric cancer, a gastric cancer heterogeneity tissue microarray was analyzed by immunohistochemistry (IHC). The TMA contained 0.6 mm tissue samples from 9 areas each of the primary cancers of 113 gastric cancer patients and 3-9 samples from matched lymph node metastases from 61 of these patients. There were 59.0% of 113 evaluable cancers without any PLAP positivity in all samples while a heterogeneous PLAP positivity was seen in 38 (34.0%) of patients. In most of the samples, heterogeneity occurred within individual TMA spots (intraregional heterogeneity) while only few cancers had a combination of distinctly negative spots and spots with a majority of unequivocally positive cells (regional heterogeneity). Intraregional heterogeneity was mostly caused by an admixture of cancer areas with a glandular growth pattern showing apical/luminal PLAP staining while solid areas of the same cancers were PLAP negative. The PLAP status of metastases was often comparable to the respective primary tumor. PLAP positivity of at least one metastasis spot was observed in 74.0% of 27 PLAP positive, but in only 6.3% of 34 PLAP negative primary tumors. Discrepancies in individual cases were again mostly caused by differences in the growth patterns. Metastases with a more solid tumor growth than seen in the primary tumors, tended to be less PLAP positive, than metastases with a glandular growth pattern. To what extent the common intraregional heterogeneity of PLAP expression will disturb the efficiency of targeted anti-PLAP therapies in gastric cancer remains to be seen.