To the Editor: Primary pulmonary enteric adenocarcinoma (P-PEAC), classified as a variant of lung adenocarcinoma with invasive mucinous adenocarcinoma, colloid adenocarcinoma, and fetal adenocarcinoma by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society, was a rare type of lung adenocarcinoma. In clinical practices, P-PEAC is easily confused with secondary pulmonary enteric adenocarcinoma (S-PEAC) that is manifested as pulmonary infiltration onset. Therefore, a retrospective study was carried out to investigate the difference of clinical manifestation, imaging presentation, immunohistochemical staining, and molecular pathological characteristics of P-PEAC and S-PEAC.
Data of inpatients diagnosed with PEAC at the 900th Hospital of the Joint Logistic Support Force, People's Liberation Army, Fujian, China, between January 2013 and December 2018 were reviewed. A total of 15 P-PEAC patients were included and compared with eight S-PEAC patients, all of them suffering from histological and immunopathological examination and a confirmed diagnosis of P-PEAC or S-PEAC. Based on the different versions of clinical tumor-node-metastasis staging performed during the aforementioned period, P-PEAC patients in our study were divided into two groups, namely, early stage (I/II) and late stage (III/IV). The primary tumors of eight S-PEAC patients confirmed by physical examination (computed tomography [CT], fluorodeoxyglucose-positron emission tomography, or fiberoptic gastrointestinal endoscope) were colon cancer (two cases), rectal cancer (two cases), gastric cancer (three cases), and cholangiocarcinoma (one case). Of all 23 patients, six patients died and six were lost to follow-up ending on January 10, 2019 (8–56 months).
The age of P-PEAC (nine males and six females) and S-PEAC (six males and two females) patients ranged from 44 to 72 years (mean age: 59 ± 8 years) and 41 to 76 years (mean age: 60 ± 11 years), respectively, without difference in gender (P = 0.495) or age of onset (P = 0.793) between P-PEAC and S-PEAC. Specifically, 13 P-PEAC and three S-PEAC patients had at least one of a wide range of clinical symptoms including cough, expectoration, hemoptysis, chest tightness, chest pain, dyspnea, fever, night sweats, throat discomfort, headache, fatigue, and enlargement of cervical lymph nodes. Cough was the most common but not specific symptom. Additionally, the positive rates of tumor marker carcino-embryonic antigen (CEA), CA19-9, and CA-125 were 71% (10/14), 50% (5/10), and 50% (5/10) in P-PEAC, and 75% (6/8), 67% (4/6), and 33% (2/6) in S-PEAC, respectively. CEA and CA19-9, although rising up apparently in more than half of patients, showed no obvious difference of them between P-PEAC and S-PEAC (CEA, P = 0.683; CA19-9, P = 0.547). Furthermore, lung lesions in most patients were predominantly single, which were distributed in the left lung (10/18), whether P-PEAC (12/15) or S-PEAC (6/8). Chest CT showed a variety of lesions, including masses (11/15 in P-PEAC vs. 3/8 in S-PEAC), nodules (3/15 in P-PEAC vs. 4/8 in S-PEAC), and limiting or diffuse pneumonic infiltrates. The difference in imaging between the two diseases was small in our study. S-PEAC is essentially a metastatic pulmonary cancer characterized by scattered nodules distributing in the basal lung area on chest CT imaging. When the number of pulmonary metastases is few, nodules are usually located in peripheral lung field. However, with only eight cases being available in our group, it did little help to study the distributions and shapes of chest CT imaging in S-PEAC patients.
P-PEACs shared some morphologic and immunohistochemical appearances with pulmonary adenocarcinoma and S-PEAC, thereby making the differential diagnosis between P-PEACs and S-PEAC challenging. Moreover, histologic subtyping can be used to distinguish P-PEAC from S-PEAC, which is essentially intrapulmonary metastasis. For immunohistochemistry, P-PEAC expresses at least one of the enteric differentiation markers (including Caudal Type Homeobox 2 [CDX2], cytokeratin [CK] 20, and mucin 2 [MUC2]), with lung adenocarcinoma markers (such as CK7 and thyroid transcription factor 1 [TTF-1]) being consistently positive in almost half the cases. CK20, MUC2, CDX2, Villin, CK7, TTF-1, and NapsinA were summarized as follows in our study: 36%, 0, 89%, 100%, 93%, 47%, and 39% in P-PEAC and 100%, 83%, 100%, 100%, 50%, 0, and 33% in S-PEAC. Our result implied Villin that also serves as a common marker for PEAC.
It was found that compared with usual lung adenocarcinoma, the positive rate of KRAS in the P-PEAC patients was higher based on the data from the published cases on P-PEAC by searching the PubMed and CBM databases up to December 31, 2018. To be more specific, the positive rate of EGFR mutations and KRAS mutations in P-PEAC patients were 4% and 43%, respectively. Similar to EGFR mutations (6% vs. 2%), KRAS mutations (22% vs. 60%) were also different between Asian and non-Asian P-PEAC patients [Supplementary Table 1, http://links.lww.com/CM9/A43]. Even more, EFGR and KRAS mutations have been clearly identified as the driver genes of non-small cell lung cancer varying among different ethnic populations. Specifically, EGFR mutations rate was as high as 30% to 40% in the Asian and 10% to 20% in the non-Asian, whereas the KRAS mutations rate was 20% to 30% in Europe and America, 8% to 10% in Asian, and 8.3% in China.[4,5] However, whether Asian or non-Asian, much higher KRAS mutation rate and much lower EGFR mutations rate in P-PEAC than the usual lung adenocarcinoma was concluded. Additionally, compared with the other types of lung adenocarcinoma, higher KRAS mutation, especially in non-Asian P-PEAC patients, might suggest its unique biological properties and the potential treatment of inhibitor targeting KRAS. To further clarify our patients’ data, ADx-ARMS KRAS assay was used to detect the KRAS mutation status in tumor tissue samples, finding all negative in eight S-PEAC and three positive in 15 P-PEAC (3/15), including codon 12 G12D (35G > A) in exon 2, codon 13 G13D (38G > A) in exon 2, codon 61 (Q61L/Q61R/Q61H) in exon 3, and codon 61 (182A > T/182A > G/183A > C/183A > T) in exon 3. Based on the results of this study, which were consistent with the data from Asian summarized from the literatures, the positive rate of KRAS was 13%, which was higher than the reported data of Chinese population (8%).
In conclusion, P-PEAC is a rare type of lung adenocarcinoma, which is difficult to be differentiated from the S-PEAC. Deeper understandings of the difference between primary and secondary PEAC can be conducive for doctors to carrying out differential diagnosis. Apart from medical history, clinical manifestations, laboratory tests, physical examinations and histopathology, immunohistochemistry, and KRAS mutations status serve as more important identifying points. Therefore, further studies are required to improve our understanding of driver gene mutations-related targeted therapy and standard chemotherapy regimen.
The authors acknowledge Zheng-An Zhu and Zai-Xin Wu from the 900th Hospital of the Joint Logistic Support Force, People's Liberation Army, for their assistance in collection and statistical analysis of data while drafting this manuscript.
This work was supported by grants from Foundation of Nanjing Military Command of People's Liberation Army (general program, No. 15MS135), Priority Project of Science and Technology Plan of Fujian Province (No. 2014Y0037), and Clinical Key Specialty Construction Project in Fujian Province (No. 2015-593).
Conflicts of interest
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