In order to better understand the pharmacology and resistance patterns behind three generations of ALK inhibitors, we sought to examine a patient with metastatic anaplastic lymphoma kinase-1-rearranged inflammatory myofibroblastic sarcoma to the brain.
One exceptional case of a RANBP2-ALK-positive epithelioid inflammatory myofibroblastic sarcoma (an aggressive variant of IMT) showed moderate cytoplasmic staining for pan-Trk.
These include gene fusions in vascular neoplasms (FOSB, CAMTA1 and TFE3), round cell sarcomas (BCOR, DUX4 and WT1), and fibroblastic/myofibroblastic tumors (STAT6, ALK and Pan-TRK); amplifications in well-differentiated and dedifferentiated liposarcomas (MDM2 and CDK4); and deletions in several aggressive neoplasms (SMARCB1 and SMARCA4).
These studies show that atypical spindle-cell IMT can utilize the same ALK fusion mechanisms described previously in conventional IMT, whereas in clinically aggressive epithelioid inflammatory myofibroblastic sarcoma we identify a novel recurrent ALK oncogenic mechanism, resulting from fusion with the RRBP1 gene.
Because anaplastic lymphoma kinase (ALK) translocation is common in sarcoma, ALK fluorescence in situ hybridization (FISH) was performed and the result was positive.
Compared with patients with ALK(-) lung adenocarcinomas (33 patients; 12 with epidermal growth factor receptor [EGFR]-mutation, 11 with Kristen rat sarcoma [KRAS]-mutation, and 10 wild-type adenocarcinomas), patients with ALK(+) adenocarcinoma presented at a younger age; and there was no correlation noted with sex or smoking status.
The identification of fusion genes such as SYT-SSX1/SSX2, PAX3-FOXO1, TPM3/TPM4-ALK and EWS-FLI1 in human sarcomas has provided important insight into the diagnosis and targeted therapy of sarcomas.
The feature of the neoplasms, including epithelioid morphology, anaplastic lymphoma kinase staining on the nuclear membrane, and results from the reverse transcriptase-polymerase chain reaction, led to diagnosis of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion.
This case suggests that echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase fusion is an oncogenic event in not only carcinomas but also sarcomas originating from stromal cells.
In details, activating epidermal growth factor receptor mutations were detected in 21 % of 311 evaluable patients, Kirsten rat sarcoma 2 viral oncogene homolog mutation in 22 % of the 77 evaluable patients and anaplastic lymphoma kinase translocations analysis was performed in 74 patients and resulted positive in 23 % of cases.
Considering tumor heterogeneity, the percentage of ALK amplified tumor cells ranged from 11% to 43%, with a mean gene copy gain (GCG ± SD) of 6.9 ± 0.8 and no signal differences between the epithelial (6.5 ± 0.9) and the sarcoma-like components (6.8 ± 0.9) of tumors.
Since the first discovery of anaplastic lymphoma kinase (ALK) in anaplastic large cell lymphoma (ALCL) by Morris et al in 1994, the number of ALK-positive neoplasms, either in the form of translocation or gain-of-function mutations, have been dramatically expanded from ALCL of T- and NK-cell origin, to diffuse large B-cell lymphoma, inflammatory myofibroblastic tumor (IMT), neuroblastoma, non-small cell lung carcinoma (NSCLC), undifferentiated anaplastic thyroid carcinoma, and rare type of sarcomas.
In summary, the epithelioid variant of IMT with nuclear membrane or perinuclear ALK is a distinctive intra-abdominal sarcoma with a predilection for male patients.
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) involved in the genesis of several human cancers; indeed, ALK was initially identified in constitutively activated and oncogenic fusion forms--the most common being nucleophosmin (NPM)-ALK--in a non-Hodgkin's lymphoma (NHL) known as anaplastic large-cell lymphoma (ALCL) and subsequent studies identified ALK fusions in the human sarcomas called inflammatory myofibroblastic tumors (IMTs).