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 Table of Contents  
Year : 2019  |  Volume : 5  |  Issue : 3  |  Page : 60-63

A patient with persistent foot swelling after ankle sprain: B-Cell lymphoblastic lymphoma mimicking soft-tissue sarcoma

1 Propath Services, Dallas, Texas, USA
2 Department of Pathology, UT Southwestern Medical Center, Dallas, Texas, USA
3 Division of Pediatric Hematology-Oncology, UT Southwestern Medical Center, Dallas, Texas, USA

Date of Submission31-May-2019
Date of Acceptance17-Sep-2019
Date of Web Publication30-Sep-2019

Correspondence Address:
Dr. Hung S Luu
1935 Medical District Drive, Dallas, Texas 75235
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ctm.ctm_22_19

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We describe a case of B-cell lymphoblastic lymphoma with an unusual clinical presentation. A 15-year old male with no significant past medical history presented with persistent foot swelling after an ankle sprain. Imaging revealed a mass in the right foot, which was resected and revealed a diffuse infiltrate of B-lymphoblasts. Peripheral blood and bone marrow examinations revealed no abnormalities. These findings were consistent with B-cell lymphoblastic lymphoma, which is an uncommon disease, accounting for only 2% of lymphomas. This case is a reminder that hematolymphoid malignancies can have presentations that mimic sarcomas with no visible peripheral blood or bone marrow involvement. In addition to describing the clinical and histologic features of this case, we also discuss the challenges that can be encountered when establishing a diagnosis of B lymphoblastic lymphoma

Keywords: B-lymphoblastic lymphoma, lymphoid neoplasm immunophenotyping, soft tissue tumor

How to cite this article:
Montgomery-Goecker CR, Martin AA, Timmons CF, Rakheja D, Rajaram V, Luu HS. A patient with persistent foot swelling after ankle sprain: B-Cell lymphoblastic lymphoma mimicking soft-tissue sarcoma. Cancer Transl Med 2019;5:60-3

How to cite this URL:
Montgomery-Goecker CR, Martin AA, Timmons CF, Rakheja D, Rajaram V, Luu HS. A patient with persistent foot swelling after ankle sprain: B-Cell lymphoblastic lymphoma mimicking soft-tissue sarcoma. Cancer Transl Med [serial online] 2019 [cited 2020 Sep 26];5:60-3. Available from: http://www.cancertm.com/text.asp?2019/5/3/60/268229

  Introduction Top

B-cell lymphoblastic lymphoma (B-LBL) accounts for approximately 10% of cases of lymphoblastic lymphoma and is much less common than T-cell lymphoblastic lymphoma (T-LBL).[1] This neoplasm is currently combined with B-cell acute lymphoblastic leukemia (B-ALL) under the 2016 World Health Organization classification.[2],[3] Traditionally, the term lymphoma has been used for nodal disease or extranodal tissue involvement with <25% bone marrow lymphoblasts.[4] While most cases of ALL are of B-cell lineage, the overwhelming majority of lymphoblastic lymphomas are of T-cell lineage.

  Case Report Top

A 15-year old male with no significant past medical history was referred to our institution for persistent right foot swelling for the past 3 months. The swelling began after the patient suffered an ankle sprain while playing basketball. He was observed at an outside institution for the sprain and was given crutches and discharged home. The patient was able to return to normal activities within a few weeks; however, he reported that the swelling persisted. After 2 months, the patient had his foot re-evaluated for continued swelling, erythema, and warmth. Imaging of the right foot revealed significant findings, including moderate soft-tissue swelling in the medial forefoot, abnormal signal in the first metatarsal and medial cuneiform, and abnormal marrow signal in the first metatarsal and cuneiform with periosteal reaction [Figure 1]. The left foot also showed an abnormal marrow signal in the cuboid with soft-tissue involvement. At that time, the patient was referred to our institution.
Figure 1: Magnetic resonance imaging of the right foot with the enhancement of the medial cuneiform and first metatarsal (a) with increased signal in the surrounding soft-tissue mass (b). This illustrates marrow surrounding soft-tissue extraosseous involvement associated with his diagnosis of lymphoma

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Physical examination at our institution showed right medial foot swelling with erythema and warmth. No skin lesions or rash was noted. A complete blood count and differential showed a white blood cell count of 6.3 × 10[9]/L; red blood cell, 5.20 10[12]/L; hemoglobin, 15.3 g/dL; hematocrit, 43.8%; mean corpuscular volume, 84.2 fL; mean corpuscular hemoglobin (MCH), 29.4 pg; MCH concentration, 34.9 g/dL; platelets, 241 × 10[9]/L; and red cell distribution width, 12.3%. His differential demonstrated 57.6% neutrophils, 31.2% lymphocytes, 8.0% monocytes, 2.2% eosinophils, and 1.0% basophils.

The patient was scheduled for surgery and underwent a biopsy of the right medial foot mass. An intraoperative consultation was performed, including a touch preparation and frozen section, and was interpreted as malignant small-round-cell tumor. Histologic sections revealed sheets of cells that infiltrated collagen, skeletal muscle, and fat. The cells were small to medium-sized with round-to-polygonal borders, scant basophilic cytoplasm, irregular nuclei, fine vesicular chromatin, and occasional distinct nucleoli [Figure 2].
Figure 2: (a) Diffuse infiltrate of small to medium-sized cells dissecting collagen and muscle and infiltrating fat. (b) Higher magnification demonstrating the round-to-polygonal borders, scant basophilic cytoplasm, irregular nuclei, fine vesicular chromatin, and occasional distinct nucleoli. The tumor shows diffuse positive staining for (c) terminal deoxynucleotidyl transferase, (d) PAX5, and (e) CD10. The cells show weak positive staining for (f) CD79a

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Immunohistochemical studies revealed that the tumor cells were positive for CD45, PAX5, CD10, CD34, CD43, CD79a (weak), terminal deoxynucleotidyl transferase (TdT), FLI1, and BAF47 [Figure 2]. The tumor cells were negative for CD99, WT1, synaptophysin, AE1/AE3, desmin, myogenin, CD3, CD20, CD117, lysozyme, and myeloperoxidase. Conventional cytogenetic analysis showed a normal karyotype. Fluorescent in situ hybridization showed no evidence of aneuploidy for chromosomes 4 or 10, no BCR/ABL1 rearrangement, no mixed-lineage leukemia rearrangement, and no ETV6/RUNX1 rearrangement.

An iliac crest bone marrow aspirate and biopsy was performed to determine marrow involvement. This revealed a normocellular bone marrow with trilinear hematopoiesis and no morphologic or flow cytometric evidence of acute leukemia. The peripheral blood and cerebrospinal fluid also revealed no evidence of disease involvement.

The patient was diagnosed with B-lymphoblastic lymphoma. A staging positron-emission tomography-computed tomography (PET CT) scan revealed metastatic foci of disease in the left cuboid and tibial diaphysis, right patella, and right trapezium, thereby establishing the disease to be Murphy stage III. He was started on treatment with Children's Oncology Group (COG) protocol AALL1131 for high-risk disease. The patient has since completed induction and consolidation chemotherapy. At the end of consolidation therapy, a PET CT scan showed no residual disease. At the time of writing of this report, he is receiving delayed intensification chemotherapy.

  Discussion Top

B-LBL is an uncommon disease that accounts for 2% of all lymphomas and only 10% of lymphoblastic lymphomas.[1] The vast majority of lymphoblastic lymphomas (90%) are of T-cell lineage. Most cases of B-LBL occur in those younger than 20 years of age and have variable presentations.[2] B-LBL most frequently involves the skin, soft tissue, bone, and lymph nodes. Other rare sites of involvement have been reported, such as the breast, stomach, colon, and ovary. In contrast to T-LBL, B-LBL rarely presents as a mediastinal mass.[3],[5]

Histologically, B-LBL is described as having a paracortical pattern in lymph nodes and a diffuse infiltrative pattern in extranodal tissues, with characteristic dissection in between collagen and skeletal muscle fibers. In nodal disease, there is usually capsular invasion. In bones, the neoplastic cells infiltrate the marrow space with periosteal fibrosis and bone remodeling. Mitoses are typically easy to identify in all cases of B-LBL. The cell morphology is identical to lymphoblasts in ALL, having small to medium-sized cells with scant basophilic cytoplasm, round-to-irregular nuclei, fine chromatin, and inconspicuous nucleoli.[1],[2],[3],[4],[5]

Immunohistochemistry and immunophenotypic analyses with flow cytometry are critical in establishing a diagnosis of B-LBL. The neoplastic cells are classically positive for B-cell markers such as CD19, CD79a, CD22, and PAX5, with variable expression of CD20. Kappa and lambda light chains are not expressed, reflecting the immaturity of the neoplastic B-cells. Other markers of immaturity are exhibited, including TdT, which is often positive, and CD34, which is variable. Most cases are positive for CD10 (common ALL antigen), while CD45 expression is typically dimly positive or negative. The markers HLA-DR and CD38 are commonly positive. The neoplastic cells are generally negative for T-cell markers such as CD1, CD2, CD3, CD4, CD5, CD7, and CD8. However, myeloid antigens such as CD13 and CD33 are occasionally positive.[1],[2],[3],[4],[5]

Genetic studies have shown that most cases of B-LBL demonstrate immunoglobulin heavy chain gene rearrangement or occasionally light chain gene rearrangement. T-cell gene rearrangements have been identified as well as in some cases of B-LBL. Hyperdiploidy is not a common finding, as opposed to B-ALL. Some cytogenetic abnormalities associated with B-ALL, including t (9;22), t (1;19), and t (4;11), have not been identified in B-LBL. However, additional chromosome 21 materials, such as trisomy or add (21), have been identified and are also frequently found in B-ALL.[1],[4],[5]

On histologic sections, the diagnosis of B-LBL may be challenging, particularly in limited tissue samples. The differential diagnosis includes T-LBL, blastoid variant of mantle cell lymphoma, and myeloid sarcoma. In addition, the common malignant pediatric round cell tumors including Ewing and Ewing-like sarcomas, alveolar rhabdomyosarcoma, and soft-tissue rhabdoid tumor may also be a consideration. T-LBL presents in the same age range as B-LBL; however, approximately 50% of cases of T-LBL present as a mediastinal mass and all cases will express at least one T-cell marker [Table 1]. The blastoid variant of mantle cell lymphoma is a disease of older individuals (60–70 years of age), is positive for CD5, FMC7, cyclin D1, and surface immunoglobulin, and is negative for TdT and CD34. Ewing sarcoma presents in childhood but is strongly and diffusely positive for CD99 with a cytoplasmic membrane pattern and negative for TdT. In contrast, B-LBL expresses TdT and the B-cell markers such as CD19, CD79a, and PAX5. There are reports of B-LBL that are positive for CD99 and negative for CD45, which may lead to a misdiagnosis of Ewing sarcoma.[4],[5],[6] It is essential to perform additional staining such as TdT, CD34, or CD79a, to establish an accurate diagnosis. Myeloid neoplasms may present at any age but more commonly present in adults. Myeloid neoplasms express myeloperoxidase and are negative for TdT. B-LBL expresses TdTand is typically negative for myeloperoxidase. B-LBL may express some myeloid antigens, which may make the distinction more difficult, but the expression of CD19, CD79a, and TdT will aid in diagnosis. Rhabdomyosarcoma can be excluded by immunohistochemical stains for desmin and myogenin, while rhabdoid tumors show the absence of nuclear staining for INI1.[4],[5],[6]

Most literature describing the prognosis of lymphoblastic lymphoma refer to T-LBL, and therefore, the prognosis of B-LBL is not well defined. In one study of 97 children and adolescents with B-LBL, the 5-year event-free survival rate was 82 ± 5%.[7] The patients in this study received an ALL-type regimen, consisting of an eight drug induction, consolidation, re-intensification, and maintenance therapy for up to 24 months.

A study of 114 pediatric patients with LBL by the Italian cooperative study group “AssociazioneItalianaEmatologiaOncologiaPediatrica” (AIEOP) included 26 patients with B-LBL.[8] Treatment changes in the protocol from a prior 1992 to 1997 AIEOP study included increased dose of upfront cyclophosphamide and methotrexate, use of L-asparaginase during induction therapy, intensive block therapy for slow responders, and late intensification (“Reinduction“ ) for patients with advanced-stage disease. The 7-year overall survival was 82 ± 4% for all patients and 83 ± 4% for B-LBL patients. The results of the study showed that treatment intensification was associated with a good outcome with limited toxicity in pediatric B-LBL patients.

Chimeric antigen receptor T-cell therapy (CAR-T) represents a new modality in the treatment of B-cell malignancies, in which engineered host T-cells have been transduced with a chimeric receptor targeting a cell surface antigen such as CD19 on the tumor cells.[9] Currently, two CAR-T products targeting CD19, tisagenlecleucel (Kymriah™), and axicabtageneciloleucel (Yescarta™) have been approved by the Food and Drug Administration.[10]

Initial response rates in patients treated with CAR T-cells were impressive compared with historical outcomes; however, more recent studies have shown that 50%–60% of patients will not achieve clinical remission or will relapse.[11] Two mechanisms for treatment failure have been identified and include loss of target antigen and lack of persistence of CD19 CAR T-cells in patients.[12]

Clinical data on 50 pediatric patients who achieved remission following anti-CD19 CAR T-cell therapy with a median follow-up of 10.6 months showed a relapse rate of 40% as a result of the loss of cell surface CD19 in 65% of the total relapses.[11] The major determinants of the persistence of CD19 CAR T-cells in patients have been found to be conditioning regimen, disease burden, and CAR costimulatory domain.[12] Most studies of CAR T-cell therapy have been conducted in patients with B-ALL rather than B-LBL; therefore, the impact of this new treatment modality on the prognosis of B-LBL remains unknown.[9],[13]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Table 1: B-lymphoblastic lymphoma versus T-cell lymphoblastic lymphoma

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Conflicts of interest

There are no conflicts of interest.

  References Top

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Borowitz MJ, Chan JK, Downing JR, Le Beau MM, Arber DA. B lymphoblastic leukaemia/lymphoma, not otherwise specified. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserijian RP, Le Beau MM, Orazi A, Siebert R, editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Lyon, France: International Agency for Research on Cancer; 2017. p. 200–2.  Back to cited text no. 3
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  [Figure 1], [Figure 2]

  [Table 1]


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