👤 Chad M Vanderbilt

Hepatoid lung carcinomas, similar to hepatoid carcinomas of other sites, are defined as extrahepatic tumors exhibiting divergent hepatocellular differentiation. Uniquely, hepatoid carcinomas of lung origin are reported to commonly express only hepatocyte paraffin 1 (HepPar1)-a hepatocellular marker, which recognizes mitochondrial enzyme carbamoyl-phosphate synthetase-1 (CPS1). Recently, HepPar1/CPS1 was found to accumulate in lung adenocarcinomas (LUADs) harboring STK11mutations, presumably as a genotype-associated metabolic adaptation. The impact of these insights on the concept of hepatoid lung carcinoma has not been explored. Here, we performed a detailed clinicopathologic and genomic analysis of carcinomas prospectively regarded as hepatoid with isolated HepPar1 expression (n = 17). We found that although robustly positive for HepPar1, these tumors were entirely negative for an extended panel of other hepatocellular markers (alpha-fetoprotein, Arginase1, Glypican3, and albumin-in situ hybridization). Morphologically, tumors exhibited solid-trabecular architecture with expanded granular-vacuolated-clear cytoplasm, thus evoking hepatoid morphology; however, focal-to-moderate intracytoplasmic mucin was consistently present, and hepatoid resemblance was variable. Pneumocytic markers (TTF1 and Napsin A) were entirely negative (except for cytoplasmic TTF1), commonly leading to diagnostic challenges at metastatic sites. Remarkably, next-generation sequencing revealed invariable STK11 mutations/loss (P < .00001 vs unselected LUAD, n > 2.5K). Patient survival was dismal (median, 5.8 vs 25 months for stage-matched LUAD, P = .0002). Tumors harbored high mitochondrial content by electron microscopy and other methods. For comparison, we reviewed conventional, predominantly acinar LUAD with HepPar1 expression (n = 22) and found that they also lacked any other hepatocellular markers, had invariable STK11 mutations/loss, increased granular cytoplasm, lower TTF1, and poor prognosis. We conclude that isolated HepPar1 expression in LUAD reflects mitochondrial adaptation to STK11 mutations rather than bona fide hepatocellular differentiation, and that HepPar1-expressing solid and granular adenocarcinomas represent an undifferentiated (solid, TTF1 negative) variant in this spectrum of tumors. Recognition of these tumors is warranted due to their exceptionally aggressive behavior, distinct pathogenomic features, and common association with diagnostic challenges. Show less

The prototype mitogen-activated protein (MAP) kinase module is a three-kinase cascade consisting of the MAP kinase, extracellular signal-regulated protein kinase (ERK) 1 or ERK2, the MAP/ERK kinase (MEK) MEK1 or MEK2, and the MEK kinase, Raf-1 or B-Raf. This and other MAP kinase modules are thought to be critical signal transducers in major cellular events including proliferation, differentiation, and stress responses. To identify novel mammalian MAP kinase modules, polymerase chain reaction was used to isolate a new MEK family member, MEK5, from the rat. MEK5 is more closely related to MEK1 and MEK2 than to the other known mammalian MEKs, MKK3 and MKK4. MEK5 is thought to lie in an uncharacterized MAP kinase pathway, because MEK5 does not phosphorylate the ERK/MAP kinase family members ERK1, ERK2, ERK3, JNK/SAPK, or p38/HOG1, nor will Raf-1, c-Mos, or MEKK1 highly phosphorylate it. Alternative splicing results in a 50-kDa alpha and a 40-kDa beta isoform of MEK5. MEK5 beta is ubiquitously distributed and primarily cytosolic. MEK5 alpha is expressed most highly in liver and brain and is particulate. The 23 amino acids encoded by the 5' exon in the larger alpha isoform are similar to a sequence found in certain proteins believed to associate with the actin cytoskeleton; this alternatively spliced modular domain may lead to the differential subcellular localization of MEK5 alpha. Show less