Philadelphia chromosome-positive acute myeloid leukemia with masses and osteolytic lesions: finding of 18F-FDG PET/CT

Abstract

Philadelphia chromosome-positive acute myeloid leukemia is controversial and difficult to distinguish from the blast phase of chronic myeloid leukemia. As a myeloid neoplasm, rare cases of this leukemia manifest multiple soft-tissue tumors or bone lytic lesions. In this paper, we describe a 49-year-old male patient who had an abrupt onset with sharp chest pain, fever, fatigue, emaciation, and splenomegaly. 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) result showed diffuse and uneven hypermetabolic lesions in the bone marrow with peripheral bone marrow expansion, multiple soft tissue neoplasms with high 18F-FDG uptake, and lytic bone lesions. Bone marrow smear and biopsy detected aberrant blast cells expressing myeloid rather than lymphoid immunophenotype marker. For the existence of Philadelphia chromosome and BCR-ABL1 fusion gene together with complex chromosome abnormalities, a diagnosis of Philadelphia-positive acute myeloid leukemia was made, although the type (de novo or blast crisis) remained unclear.

Keywords

Philadelphia chromosome / acute myeloid leukemia / mass / osteolysis / positron emission tomography

Introduction

The Philadelphia chromosome (Ph) is a basic pathognomonic feature for chronic myeloid leukemia (CML). A confusing entity, de novo Ph⁺acute myeloid leukemia (AML), with a prevalence of 0.35%–0.9% [1], has been controversial because it cannot be exactly distinguished from the blast phase of CML. Some researchers believes de novo Ph⁺ AML does not exist, i.e., it is similar to the blast phase of CML (CML–BP) onset without chronic phase, whereas the opponents suppose that each of them is an independent entity.

Of all the adult myeloid neoplasms, mostly bone marrow and peripheral blood were involved. However, in very few cases, extramedullary involvement, such as soft-tissue tumor or osteolysis, can be found, especially in CML, Ph⁺ MDS, or AML reported all over the world. We recently observed a 49-year-old man with Ph⁺ AML, in whom multiple osteolytic lesions with soft-tissue tumors were presented simultaneously by 18F-fluoro-deoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan at the onset of the disease. However, neither de novo nor blastic crisis from CML was exactly concluded.

Presentation of case

A 49-year-old man with no medical history and with chest pain for two weeks was presented. Physical examination revealed a tumor on the lower front of the right side of the chest wall (diameter: 5 cm× 6 cm) and splenomegaly (7 cm below costal margin).

Blood count showed 25.03×10⁹/L, 63 g/L, and 71×10⁹/L for white blood cell, hemoglobin, and platelet, respectively. The blood film showed that the percentages of increased blasts, promyelocytes, and monocytes were 28%, 9%, and 1%, respectively (Fig. 1A). Bone marrow aspirate smear showed hyperplasia of granulopoesis, and the myeloid-erythroid ratio was 5.71:1. Blast cells, progranulocytes, neutrophilic myelocytes, eosinophils, basophils, and monocytes accounted for 26%, 3%, 10.5%, 1%, 1%, and 3%, respectively (Fig. 1B). Blast cells were positive for peroxidase and weakly positive for nonspecific esterase stain. The neutrophil alkaline phosphatase score was 67.

The biopsies of the bone marrow and soft tissue-mass close to the 8th right rib (the largest hot spot in 18F-FDG PET/CT scan) morphologically resembled the bone marrow smear. Immunohistochemistry showed blasts positive for myeloperoxidase, CD34, CD117, and CD43, and negative for CD3, CD7, CD20, CD79a, CD38, CD138, CD235a, TDT, MUM-1, and PAX-5. Flow-cytometric immunophenotyping revealed blasts positive for CD13, CD33, and CD34. The karyotype analysis revealed the Philadelphia chromosome in all the cells analyzed, and additional aberrations were detected in 10 of the total 11 cells, i.e., 46, XY, t(9;22)(q34;q11)[1]/44-45, idem, -1, -7, +8, +10, -17, -18, + mar1, and+ mar2 [CP10] (Fig. 1C). BCR-ABL1 fusion gene (b3a2 type) was detected by RT–PCR obtaining a BCR-ABL1/ABL1 ratio of 61.9%, and no mutation was found by sequencing (Fig. 1D). NPM1, FLT3-ITD, and C-KIT mutations were not detected.

Whole body 18F-FDG PET/CT showed multiple hypermetabolic foci. Transverse 18F-FGD-PET/CT fusion images showed better anatomical features of the 18F-FDG-avid lesions. PET showed diffused and heterogeneous intense 18F-FDG uptake lesions with maximum standardized uptake value (SUVmax) up to 9.1 in the bone marrow, and CT displayed density heterogeneously increased in those abnormal metabolic foci (Fig. 2A). Interestingly, 18F-FDG PET/CT showed multiple 18F-FDG-avid soft tissue density nodules and masses in many sites, such as bilateral chest walls, around the sternum and spine, and the thoracic and abdominal subcutaneous space. The biggest soft-tissue mass was located in the right chest wall with SUVmax up to 10.8. The 8th right rib was demonstrated with osteolytic destruction. Splenomegaly was also observed (Fig. 2B).

The working diagnosis of Ph⁺ AML (M2 type according to FAB system) was made, either de novo or CML onset in blastic crisis. The patient refused treatment with the tyrosine kinase inhibitor. He accepted three cycles of combined chemotherapy in three months, and the drugs were selected from idamycin, pirarubicin, homoharringtonine, cytosine arabinoside, and cyclophosphamide, while curative effect appeared slightly. Four months after diagnosis, the patient died from dyscrasia and infection.

Discussion

Nowadays, whether Ph⁺ AML is a distinct clinicopathologic entity remains controversial. The 4th edition of the World Health Organization (WHO) classification does not recognize Ph⁺ AML [2]. Philadelphia chromosome positive myelodysplasia syndrome (Ph⁺ MDS) may be found [3]. Over the past several decades, some researchers have thoroughly evaluated this issue. These studies emphasize routine clinical and laboratory characteristics. As described, patients with CML–BP were more likely to have basophilia and splenomegaly than patients with Ph⁺ AML [4–6], and the former had higher bone marrow cellularity and myeloid/erythroid ratios. Some studies found leukocytosis seemed more distinct in Ph⁺ AML. Additional cytogenetic abnormalities that usually occur in CML–BP were less common in Ph⁺ AML [5]. Either M-BCR or m-BCR gene rearrangements occurred in Ph⁺ AML, though the former appears to be more common than the latter [5,7]. Moreover, after induction chemotherapy, patients with Ph⁺ AML tend to return to a normal karyotype more easily than those with CML-BP [7]. The median survival of patients with CML-BP was similar to that of patients with Ph⁺ AML [5]. Not all the suggested differences between the two disorders were absolute. In fact, they exhibited overlapped characteristics obviously or slightly, thus, except for statistical significance, no diagnostic criteria can be formed based on these results. Recently, four-base-pair (TCTG) insertion consistent with a type A mutation of the NPM1gene was observed in two of nine patients with Ph⁺ AML. In contrast, none of the patients with CML-BP had NPM1 mutations [8]. Perhaps the expectation to discriminate between the two entities should rely on high throughput genome screening. Nacheva et al. applied genomic arrays and found 100% loss of the immunoglobulin sequences (IGH/VDJ gene regions) in Ph⁺ AML but not in myeloid blast crisis of CML, which were almost always accompanied by deletions of T cell receptor genes (TRG) @TARP (alternate reading frame protein). This result is interesting, and confirmation may be executed in large samples [9,10].

Soft-tissue tumor formation and bone lesion are rare phenomena in both Ph⁺ and Ph⁻ myloid leukemias. Both chronic phase and blast crisis of CML could demonstrate osteolysis, sometimes shortly before blast crisis as a precursor. Only one case of Ph⁺ MDS characterized by lytic foci throughout the axial skeleton was reported [11]. At present, no paper on the formation of mass or osteolysis in Ph⁺ AML has been published. In literatures, such subjects manifested only one sort of complication, either bone lesion or solid tumor. Coexistence of these two lesions in one patient, as described in this paper, was not mentioned previously.

Without exception, all the reported CML cases presented with osteolysis occurring with blastic transformation simultaneously were preceded by chronic phase. Thus, differentiating Ph⁺ AML from CML was unnecessary. In contrast, the case we described displayed an abrupt onset of acute myeloid neoplasm and lack of preceding chronic phase. Although he showed obvious splenomegaly, the inexistence of basophilia or eosinophilia confused the diagnosis.

18F-FDG PET/CT is an advanced molecular imaging technique that merges functional with anatomic imaging to optimize disease assessment, which is gradually applied in the evaluation of hematopoietic disorders. Extensive infiltration in the bone marrow, multiple soft-tissue neoplasms, and osteolytic lesion in the 8th right rib with high 18F-FDG uptake was shown in this case as a result of the high sensitivity and broad coverage of 18F-FDG PET/CT. The rare manifestation indicated an invasive pattern of disease progression. In a study by Cribe et al., 18F-FDG PET scans detected more than twice as many patients with extramedullary disease than those discovered by clinical examination. Moreover, several patients who had early relapse reached complete remission (CR) in the bone marrow but only obtained partial remission with PET [12]. Vanderhoek et al.investigated the value of 3′-deoxy-3′-[(18)F]fluoro-l-thymidine (FLT) PET for early assessment of therapy response in patients with AML. Both during and after therapy, AML patients who reached CR displayed low FLT uptake in the bone marrow, whereas patients with resistant disease showed higher uptake. Interestingly, patients with resistant disease showed higher FLT uptake versus those with CR as early as two days after the beginning of chemotherapy [13]. Consequently, 18F-FDG PET/CT is extremely helpful in evaluating the disease objectively and comprehensively.

Conclusions

Coexistence of multiple masses and osteolytic lesions in a case with Ph⁺ AML, which has not been reported before, is described in this paper. Further studies are necessary to ensure the recognition of de novo Ph⁺ AML as a distinct entity.

References

[1] Frankfurt O, Platanias LC. Philadelphia chromosome positive acute myeloid leukemia or de novo chronic myeloid leukemia-blast phase? Leuk Lymphoma 2013; 54(1): 1–2

[2] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC, 2008

[3] Dutta S, Kumari P, Natraj KS, Mandal PK, Saha S, Bagchi B, Choudhuri S, Dolai TK. Philadelphia chromosome-positive myelodysplastic syndrome: is it a distinct entity? Acta Haematol 2013; 129(4): 215–217

[4] Berger R. Differences between blastic chronic myeloid leukemia and Ph-positive acute leukemia. Leuk Lymphoma 1993; 11(Suppl 1): 235–237

[5] Soupir CP, Vergilio JA, Dal Cin P, Muzikansky A, Kantarjian H, Jones D, Hasserjian RP. Philadelphia chromosome-positive acute myeloid leukemia: a rare aggressive leukemia with clinicopathologic features distinct from chronic myeloid leukemia in myeloid blast crisis. Am J Clin Pathol 2007; 127(4): 642–650

[6] Cuneo A, Ferrant A, Michaux JL, Demuynck H, Boogaerts M, Louwagie A, Doyen C, Stul M, Cassiman JJ, Dal Cin P, Castoldi G, Van den Berghe H. Philadelphia chromosome-positive acute myeloid leukemia: cytoimmunologic and cytogenetic features. Haematologica 1996; 81(5): 423–427

[7] Keung YK, Beaty M, Powell BL, Molnar I, Buss D, Pettenati M. Philadelphia chromosome positive myelodysplastic syndrome and acute myeloid leukemia-retrospective study and review of literature. Leuk Res 2004; 28(6): 579–586

[8] Konoplev S, Yin CC, Kornblau SM, Kantarjian HM, Konopleva M, Andreeff M, Lu G, Zuo Z, Luthra R, Medeiros LJ, Bueso-Ramos CE. Molecular characterization of de novo Philadelphia chromosome-positive acute myeloid leukemia. Leuk Lymphoma 2013; 54(1): 138–144

[9] Nacheva EP, Grace CD, Brazma D, Gancheva K, Howard-Reeves J, Rai L, Gale RE, Linch DC, Hills RK, Russell N, Burnett AK, Kottaridis PD. Does BCR/ABL1 positive acute myeloid leukaemia exist? Br J Haematol 2013; 161(4): 541–550

[10] Reboursiere E, Chantepie S, Gac AC, Reman O. Rare but authentic Philadelphia-positive acute myeloblastic leukemia: two case reports and a literature review of characteristics, treatment and outcome. Hematol Oncol Stem Cell Ther 2015; 8(1): 28–33

[11] Tucker D, Hamilton MS, Kerr JP, Wickham C, Hunter H. Lytic bone disease as the presenting feature of Philadelphia-positive monosomy 7 myelodysplasia progressing to acute myeloid leukaemia. Gene 2012; 501(2): 219–221

[12] Cribe AS, Steenhof M, Marcher CW, Petersen H, Frederiksen H, Friis LS. Extramedullary disease in patients with acute myeloid leukemia assessed by 18F-FDG PET. Eur J Haematol 2013; 90(4): 273–278

[13] Vanderhoek M, Juckett MB, Perlman SB, Nickles RJ, Jeraj R. Early assessment of treatment response in patients with AML using [(18)F]FLT PET imaging. Leuk Res 2011; 35(3): 310–316

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