Blast phase in chronic myelogenous leukemia (CML) has rarely been reported to involve extramedullary sites like skin, lymph nodes, and central nervous system. Clinical history, characteristic hematologic findings (elevated leukocyte counts, myelocytic predominance, and basophilia), and Philadelphia chromosome are of high diagnostic significance especially in isolated extramedullary presentations. We describe a unique case of CML relapse with blast phase involving the eye. A 66-year-old man with a known diagnosis of CML on imatinib and in molecular remission for 3 years presented with a painful blind eye. Histologic examination revealed diffuse involvement of choroid, iris, vitreous humor, and the optic nerve by blast cells. The blasts expressed CD34, aberrant TdT, and a myeloid phenotype (CD13, CD33, and CD117). Fluorescence in situ hybridization (FISH) of vitreous fluid detected
Blast crisis in CML is defined by the presence of ≥20% blasts in the bone marrow or peripheral blood, large clusters of blasts in the bone marrow biopsy, or any extramedullary blast proliferation [
Our patient is a 66-year-old male who was first diagnosed with CML after presenting to the emergency room with acute onset knee pain. During the investigation, he was found to have an elevated white blood cell count (64.4 × 109/L). The differential count revealed neutrophilia with left shift and basophilia. A subsequent bone marrow biopsy showed morphologic features consistent with chronic phase of CML. Conventional karyotyping and fluorescence in situ hybridization (FISH) on the bone marrow aspirate (Figure
He remained in remission for three years after initial diagnosis, when he presented with sudden onset pain and loss of vision in the right eye. Magnetic resonance imaging (MRI) scan showed significant intraorbital and optic nerve enhancement. An infratemporal intraconal fat and intraorbital fat biopsy was negative for malignancy. The patient’s symptoms improved with conservative management by posterior chamber decompression and steroid therapy but his vision never returned to baseline following this episode. A follow-up MRI 2 months later showed no residual signs of enhancement. Eight months following this episode, he presented with recurrent pain in the right eye, which did not resolve with conservative management. As a result, the patient underwent enucleation of his right eye.
On gross examination, a cross section of the eye showed diffuse circumferential thickening of the choroid (Figure
Gross photomicrograph depicting pupil-optic nerve (PO) section of enucleated eye which reveals diffuse thickening of the iris and part of the choroid layer.
Blasts cells infiltrating the iris (H&E, magnification ×20).
Sheets of monotonous mononuclear blast cells (H&E, magnification ×400).
Flow cytometric immunophenotypic analysis of vitreous fluid: blast gate (P4 gate in the top line) represents the dim CD45+ cells with low side light scatter (SSC). Blast gate (P3 gate in the bottom line) represents the same population of blasts analyzed for cytoplasmic markers in a separate tube. The distinct cluster of blasts (red color population) exhibit the following immunophenotypic characteristics:
CD34 immunohistochemistry: sheets of monotonous CD34 positive blast cells (magnification ×400).
CD117 immunohistochemistry: focal and variable intensity of CD117 expression is seen in the blasts (magnification ×400).
TdT immunohistochemistry: sheets of blasts showing nuclear expression of TdT (magnification ×400).
Fluorescence in situ hybridization assay on vitreous humor smear shows two BCR-ABL1 fusion signals, one BCR probe signal, and two ABL1 probe signals; thus a t(9;22) BCR-ABL1 gene rearrangement with gains of 9 and 22 [orange = 9q34 ABL1 probe; green = 22q11.2 BCR probe].
Fluorescent in situ hybridization on original diagnostic bone marrow aspirate shows one BCR-ABL1 fusion signal, two BCR probe signals, and three ABL1 probe signals in 90.5% of interphase cells.
Extramedullary blast crisis in CML is a rare occurrence. In a study of 235 CML patients by Specchia et al. [
In our case, the patient was treated with cytarabine/doxorubicin and intrathecal methotrexate. Imatinib mesylate is considered first-line therapy for treatment of CML in chronic phase with majority of patients achieving complete cytogenetic and major molecular response. Sudden evolution of disease into blast phase can rarely occur while the patient is on imatinib therapy [
In our patient, the chromosome study was positive for t(9;22)(q34;q11) translocation, FISH showed
At the time of relapse, in addition to t(9;22)(q34;q11) reciprocal translocation (Ph+), our patient demonstrated other chromosomal aberrancies including trisomy 8 and gains of chromosomes 9 and 22. Trisomy 8 has been frequently associated with clonal evolution in CML patients on imatinib who are otherwise in complete cytogenetic remission [
Using whole genome sequencing, Calabretta and Perrotti [
While extramedullary manifestation of CML is rare, a high degree of suspicion is warranted in patients with CML on imatinib therapy who manifest CNS or ocular symptoms, even in the absence of any hematologic, cytogenetic, or molecular evidence of disease. Despite advances in molecular disease detection, more sensitive and effective methods of monitoring disease progression are still needed.
Chronic myelogenous leukemia
Fluorescent in situ hybridization
Central nervous system
Polymerase chain reaction
Magnetic resonance imaging
Food and Drug Administration.
The above study was approved by the Institutional Review Board at Henry Ford Hospital, Detroit, Michigan, USA.
Written informed consent was obtained from the patient for publication of the case report and any accompanying images.
The authors declare that they have no competing interests.
Rohit Gulati did the data collection, grossing of the surgical specimen in patient care, drafted the paper, and reviewed literature. Yaser Alkhatib helped in data collection from clinical aspects and helped in formulation of the paper. Michelle Madden Felicella conducted the grossing of the specimen supervising Rohit Gulati, helped in paper completion, and took images of the surgical specimen. Vijayalakshmi Donthireddy is the oncologist of the patient and helped collect pertinent points of patient clinical history and completing the paper. Madhu P. Menon played a significant role in paper completion and critically analyzing the review of the literature. Kedar V. Inamdar is the primary hematopathologist for the case and played a significant role in data collection, selecting microscopic images, critically analyzing the data, and reviewing literature and paper preparation.