Case Report

Aggressive T-cell Large Granular Lymphocytic Leukemia Presenting as an EBV Negative Post-Transplant Lymphoproliferative Disorder

Leeborg N1, Loriaux M1 and Huang JZ2*
1Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR, USA
2Department of Clinical Pathology, William Beaumont Hospital, Royal Oak, MI, USA and Department of Pathology and Laboratory Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, USA


*Corresponding author: James Z Huang, Department of Clinical Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA


Published: 30 May, 2016
Cite this article as: Leeborg N, Loriaux M, Huang JZ. Aggressive T-cell Large Granular Lymphocytic Leukemia Presenting as an EBV Negative Post-Transplant Lymphoproliferative Disorder. Clin Oncol. 2016; 1: 1007.

Abstract

A 33 year-old man, a renal transplant recipient, developed an aggressive T-cell large granular lymphocytic leukemia (LGL) that presented as a soft-tissue lesion, mimicking an abscess. The tumor cells showed cytological features of large granular lymphocytes, immunophenotypically characterized as mature T-cells expressing CD2, CD5, CD4, CD56, and TIA-1. About 80% of tumor cells were positive for Ki-67 and p53. Cytogenetic analysis demonstrated trisomy 8, trisomy 15, and trisomy 21. There was no evidence of Epstein-Barr virus infection. The patient died 14 days after diagnosis with multiple organ failure and extensive bone marrow and visceral involvement.

Keywords: T-cell large granular lymphocytic leukemia; Post-transplant lymphoproliferative disorder

Introduction

T-cell large granular lymphocytic leukemia (T-LGL) rarely occurs as a post-transplant lymphoproliferative disorder (PTLD) [1-7]. Its pathological features, clinical course, and genetic abnormalities have not been yet well defined in this setting; nor has a role for Epstein-Barr virus (EBV). The current case reports a renal transplant recipient who presented with a soft-tissue lesion, clinically mimicking infection with an abscess formation. Pathology evaluation showed extensive soft-tissue necrosis associated with infiltration of mature T cells with a high proliferation index and expression of CD2, CD3, CD4, CD56, TIA-1 and p53. Large granular lymphocytes with the same immunophenotypic features were in both peripheral blood and bone marrow. Cytogenetic analysis demonstrated trisomy 8, trisomy 15, and trisomy 21. There was no evidence of EBV association. The clinical course was very aggressive and the patient died 14 days after diagnosis, with extensive visceral involvement.

Case Report

A33-year-old male had Alport's syndrome and consequent a cadaveric renal transplantation. He was receiving Cyclosporin, Azathioprine (Imuran), and prednisone as maintenance therapy due to mild-to-moderate chronic cellular rejection. He presented to a local hospital 11 years after the renal transplantation with painful right facial swelling that was initially believed to be an abscess. The lesion was incised and drained. No cultures were obtained; however, an infectious etiology was suspected and the patient was discharged on Augmentin. Over the course of a few days, the swelling and pain continued to increase, and the patient developed a fever (103.7°F), chills, and erythema of the overlying skin. Imaging studies revealed subcutaneous edema extending from the oropharynx into the deep adipose tissue of the right lateral neck. There was no distinct abscess, well-defined mass, or lymphadenopathy. Despite enhancing the antibiotic coverage and repeated incision and drainage, the swelling did not improve. The patient was then transferred to our institution for further diagnosis and treatment. On physical examination, approximately three weeks after first presentation, the right face/neck mass measured 12 x 5 cm and was erythematous, firm, indurated, and tender but without fluctuance. Two additional tender but mobile lymph nodes (1 cm in size) were palpated in the right axilla, but these were not biopsied. There was no additional lymphadenopathy and no hepatosplenomegaly. Repeat imaging showed edema in the superficial and deep soft tissue in the right side of the neck, including inflammation of the massiter muscle, the submandibular gland, the sternocleidomastoid muscle, the platysma, and investing fascia.
There was no focal abscess, phlegmon, fluid collection, well-defined or cervical lymphadenopathy. A complete blood count at the time of admission showed a white blood cell count of 8K/cu mm with a normal differential, hematocrit of 40%, and platelet count of 260 K/ cu mm. The patient was admitted with presumed cellulitis of right face and neck, and antibiotic coverage was increased to include vancomycin, clindamycin, and cefazolin. Subsequent blood cultures and cultures of the involved facial tissue were negative. Viral serology for hepatitis A, hepatitis B, hepatitis C, cytomegalovirus, EBV, herpes simplex and human immunodeficiency virus was also negative. A skin biopsy of the right neck was obtained and showed mild vascular ectasia and congestion of the superficial venous plexus. No primary inflammatory process or neoplastic infiltrate was present. There was no evidence of graft-versus-host disease, opportunistic infection, or viral cytopathic effect of the skin. Over the next few weeks, the patient developed excruciating right neck pain. Serial blood counts revealed an increasing leukocyte count, up to 21.5 K/cu mm, with an absolute lymphocyte count reaching 19.9 K/cu mm and an absolute neutrophil count and hemoglobin nadir of 0.4 K/cu mm and 9.8 g/ dL, respectively. He also developed a thrombocytopenia with the lowest platelet count being 29.0 K/cu mm. A peripheral blood smear demonstrated a lymphocytosis, with predominantly large granular lymphocytes (Figure 1). The flow cytometric analyses revealed an abnormal mature T-cell population expressing CD2, CD3, CD4, and CD56. This population was negative for CD5, CD7, CD16, CD57, CD1a, CD10, CD34, CD117 and TdT. A diagnosis of T-cell large granular lymphocytic leukemia was established. Southern blot analysis showed clonal rearrangement of the T-cell receptor beta gene. Additional biopsies of the right neck subcutaneous fat, platysma, subplatysmal fat, and sternocleidomastoid muscle demonstrated necrosis associated extensive infiltration by leukemic cells (Figure 2) with the same immunophenotype of leukemic cells identified in the peripheral blood. Immunohistochemical stains confirmed the immunophenotype of T-cells containing cytotoxic granules, positive for TIA-1. About 80% of tumor cells were positive for Ki-67 and p53 (Figure 3). In situ hybridization studies showed no evidence of EBV infection. Bone marrow evaluation (Figure 4) showed a hypercellular marrow with extensive interstitial infiltration by tumor cells with same immunophenotype. Cytogenetic analysis revealed a complex abnormal karyotype, including additional copies of chromosomes 8, 15 and 21. Chemotherapy was initiated after the diagnosis, but the patient quickly developed acute renal failure, profound metabolic acidosis, and hepatic failure. He died 14 days after the diagnosis of T-cell LGL, just 41 days after first noticing the mass. At autopsy, there was extensive leukemic involvement of the spleen, liver, bone marrow, native and allograft kidneys, heart, adrenals, gastrointestinal tract and pancreas. There was no evidence of lymphadenopathy or additional soft-tissue masses.


Figure 1

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Figure 1
The peripheral blood smear showing leukemic lymphocytes ranging in size from small to large, with abundant cytoplasm and variable numbers of azurophilic granules. Some of the lymphocytes showed a prominent nucleolus or multiple nucleoli with coarse or condensed chromatin (magnifications: x1000).



Figure 2

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Figure 2
The biopsy of the neck mass showing extensive infiltration in the soft tissue and skeletal muscle (magnifications: A. x100 and B. x 630).



Figure 3

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Figure 3
The immunostains with tissue from the neck mass with antibodies against CD3 (A), Ki67 (B), p53(C), and TIA-1(D). Tumor cells are positive for CD3, Ki-67, p53 and TIA-1 (magnification, x 400).



Figure 4

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Figure 4
Figure 4: The bone marrow core biopsy showing hypercellularity and extensive lymphoid infiltrate (magnifications: A. x100 and B. x 630).


Discussion

The case we report here is of a very aggressive post-transplant T-cell LGL. One of unique clinical features is the initially presentation as a soft tissue mass, mimicking an abscess, in the absence of significant lymphadenopathy, splenomegaly and unremarkable automatic CBC and differential. In the cases like this, the diagnosis may be delayed if PTLD is not included in the differential diagnosis. A peripheral smear examination is of diagnostic value because large granular lymphocytes may be increased seen even total lymphocyte count is not increased. Immunophenotypic analysis of peripheral blood or involved tissue by flow cytometry allows quickly identify abnormal T-cells, leading a definitive diagnosis with or without additional molecular analysis for T-cell clonality. More importantly, immunophenotypic features of large granular T-cells are of prognostic significance. Based one previously reported cases listed in Table 1, leukemic cells of indolent cases almost are always positive for CD57 and negative for CD56. In contrast, leukemic cells of aggressive cases are always almost negative for CD57 and often positive for CD56. Loss of surface CD3 and CD5 is also seen in a subset of aggressive cases. Although EBV infection can be detected in both indolent and aggressive cases, the majority of post-transplant T-LGL cases are negative for EBV infection, suggesting EBV may not play a significant role in pathogenesis, unlike B-cell PTLD. At the genetic or molecular level, very little is known about post-transplant T-LGL. There are very few reports of cytogenetic findings in cases of post transplant T-cell LGL [2,6,7], including t [8,14] (q24;q24), isochromosome 7q, and trisomy 1, and trisomy 7. No consistent abnormalities have yet been described. Our case showed overexpression of protein p53, suggesting presence of a p53 gene mutation, which may play a role in the pathogenesis and its aggressive clinical course in this case. Additional copies of chromosomes 8, 15, and 21 were also detected in the tumor cells of this case, suggesting that the genetic lesions of T-LGL could be quite complex, highly variable. Further documentation of clinical pathological features, immunological and genetic abnormalities such rare cases as PTLD would be important for identifying possible prognostic factors, recurrent genetic abnormalities, and appropriate treatments.


Table 1

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Table 1
The immunological features of post transplant large granular lymphocytic leukemia reported in the literature.

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