As cancer therapeutics increasingly target molecular alterations, testing for somatic changes in cancer is becoming an integral part of pathology evaluations. While these somatic alterations may only be present in a small subset of a given tumor type, patients with these genetic changes often show dramatic responses when treated with targeted agents [1, 2]. Single gene assays evaluating genes such as EGFR in lung adenocarcinoma or BRAF in melanoma are now performed routinely. However, a more comprehensive tumor profiling approach has the advantage of potentially identifying a breadth of actionable genetic alterations [3, 4]. Moreover, these gene panels for somatic testing can identify unexpected genetic changes in cancer types not generally associated with a given somatic alteration.

At the Center for Advanced Molecular Diagnostics (CAMD) at Brigham and Women’s Hospital, a targeted next generation sequencing assay (OncoPanel) is performed in a Clinical Laboratory Improvement Amendments-certified laboratory to detect somatic mutations, copy number variations, and structural variants across 300 cancer-associated genes. For all patients presenting to Dana Farber Cancer Institute who are likely to require systemic therapy, informed consent is obtained, tumor adequacy is assessed, and Oncopanel is run to obtain a somatic profile for the patient’s cancer.

Here, we report a case of a 33-year-old man with myeloid sarcoma that was refractory to six different chemotherapy regimens. His tumor was analyzed using OncoPanel, and a FIP1L1-PDGFRA rearrangement was detected. As hematologic malignancies with this rearrangement are known to be responsive to imatinib therapy, he was placed on imatinib as soon as the rearrangement was reported. He responded rapidly to this course of treatment and currently shows no evidence of residual disease. This case is an example of an unanticipated finding detected through clinical high throughput somatic sequencing that tremendously affected a patient’s care and outcome.

The finding of a FIP1L1-PDGFRA rearrangement in a patient with refractory myeloid sarcoma was an unexpected finding only discovered because of clinical gene panel testing that is performed on all malignancies presenting to our institution. FIP1L1-PDGFRA was first discovered as a recurrent rearrangement in Hypereosinophilic Syndrome in 2003, and response to imatinib was demonstrated [7]. As the spectrum of malignancies associated with this rearrangement expanded, the 2008 WHO classification developed a category for these neoplasms, “Myeloid and lymphoid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1 [8]”. Since our patient did not have peripheral eosinophilia, there was no indication to order specific testing for the FIP1L1-PDGFRA rearrangement. In retrospect, the initial lymph node biopsy showed a variety of cell types admixed with myeloblasts, including plasma cells, small lymphocytes, and abundant eosinophilic forms. However, these findings alone would likely be insufficient to prompt single gene testing for PDGFRA, PDGFRB, or FGFR1.

The FIP1L1-PDGFRA fusion results in a constitutively activated tyrosine kinase and, in hematopoietic cells, results in growth factor-independent growth [7, 9]. The break points within FIP1L1 vary widely, but the break points within the PDGFRA gene are tightly clustered in exon 12, resulting in the disruption of the autoinhibitory juxtamembrane domain and activation of the kinase [10]. On our next generation sequencing panel, the base pair resolution of our translocation assay showed that this patient’s rearrangement occurred between intron 10 of FIP1L1, and exon 12 of PDGFRA. Therefore, the coordinates of the rearrangement predict the disruption of the juxtamembrane domain and kinase activation in this patient.

The diagnosis of acute myeloid leukemia or myeloid sarcoma with a FIP1L1-PDGFRA rearrangement is extremely rare, with only a handful of case reports in the literature [11–13]. The largest case series of patients with AML and a FIP1L1-PDGFRA rearrangement consists of 5 patients, all of whom achieved complete molecular remission with imatinib [14]. All of the patients described had histories of peripheral eosinophilia, which prompted targeted testing for the FIP1L1-PDGFRA rearrangement, since this rearrangement is cryptic and cannot be detected by conventional karyotype. The more widespread adoption of gene panel approaches may reveal that this rearrangement is also present in hematologic neoplasms with more subtle eosinophil findings, such as in our case.

The importance of detecting the FIP1L1-PDGFRA rearrangement in hematopoetic neoplasms cannot be understated as this fusion protein is exquisitely sensitive to imatinib. In this case, our patient had exhausted all conventional therapy for myeloid sarcoma and, until the discovery of this rearrangement by high throughput sequencing, was imminently terminal. As the number of therapeutics targeting specific genetic alterations increases and the use of gene panel testing for somatic changes expands, this scenario of unanticipated findings dramatically affecting a patient’s clinical course is bound to be repeated to the benefit of cancer patients. Moreover, NGS based somatic sequencing is increasingly being used both to direct patients into clinical trials that target the specific molecular alterations found in their tumor and as biomarkers to associate clinical response to therapy with genetic profiles [15]. The clinical utility of this testing might be enhanced for rare cancers or atypical presentations where current evidence for guiding therapy is limited and genomic characterizations may assist with treatment decisions [16]. The case report presented here highlights the importance of broad molecular analysis in cancer, especially in cases that may display atypical features, either clinically or pathologically.