ALK-Positive Lung Adenocarcinoma With Suspected Transformation to Squamous Cell Carcinoma in Lymph Node Metastases.

Comment
This report documents a rare instance of histologic transformation of ALK-rearranged lung adenocarcinoma occurring in the absence of prior ALK inhibitor exposure. Several potential causes for histologic transformation in metastatic lymph nodes are indicated. The first is the coexistence of adenocarcinoma and squamous components in the primary lung tumor. Approximately 4% to 9% of NSCLC cases contain mixed adenomatous and squamous pathologic changes in a single lesion, clinically termed adenosquamous cell carcinoma. These 2 components frequently share identical oncogenic mutations.2 Therefore, we histologically examined the primary lung lesion in detail using immunostaining for p40; however, no SCC component was observed. The second potential cause is the development of a synchronous second primary cancer, which is a carcinoma of unknown origin in the mediastinal lymph node. Nevertheless, because ALK-positive SCC occurs in approximately 2% of cases,3 it is seldom observed under conditions in which multiple lung cancers of different histologic types are simultaneously present. The third potential cause is metaplastic transformation. This mechanism is a complex process involving genetic and molecular changes within cancer cells, leading to difficult therapeutic choices and a poor prognosis. Although the underlying mechanism is unknown because of the lack of treatment pressure, early evidence supports the idea that histologic changes are the result of genomic evolution in specific pathways. A previous report showed that genomic alterations in transformed SCC could be related to the PI3K/AKT/mTOR pathway after TKI treatment of EGFR-mutated lung adenocarcinoma.4 In our case, EML (echinoderm microtubule associated protein like 4) ALK (variant ID: E6aA20.AB374361.1 and E6ins18A20.1) and TP53 (variant ID: COSM43697) were detected in the transformed SCC, and no PTEN, PIK3CA, or AKT gene mutations were observed. Unfortunately, genetic testing of the adenocarcinoma could not be validated because 3 years had passed since the resection.
Transformation to other histologic types has been reported after TKI and ICI therapy. However, to the best of our knowledge, there have been no reports of the transformation of ALK-rearranged lung adenocarcinoma in the absence of these treatments. Hsieh and coworkers5 reported 2 cases of transformation from adenocarcinoma to SCC with EGFR mutations without the development of resistance. One proposed mechanism is that tumors may contain pluripotent tumor stem cells that differentiate after TKI treatment. In our case, the patient had no history of treatment with TKIs or ICIs; however, differentiation may have progressed for some reason. In addition, there have been reports of transformation accompanied by drug resistance,6 but no apparent drug resistance was noted in this case.