Epstein-Barr virus positive peripheral T cell lymphoma with novel variants in STAT5B of a pediatric patient: a case report

Peripheral T cell lymphoma, not otherwise specific (PTCL-NOS) is the most common type of T cell lymphoma in adulthood which is account for 25.9% in Western countries [1]. However, as a variant of PTCL-NOS, Epstein-Barr virus-positive peripheral T cell lymphoma (EBV + PTCL) is a rare type which mainly occurs in the elderly with common primary site of lymph nodes and aggressive clinical course [2]. Additionally, for pediatric patients, anaplastic large cell lymphoma (ALCL) is the most common type non-Hodgkin lymphoma while PTCL-NOS only occupied 1.3% of the patients with non-Hodgkin lymphoma. Although EBV- associated T/NK lymphoproliferative disorder also occupied a large part in Asian pediatric patients [3], EBV + PTCL is extremely rare, with only 4 patients (including this case) of childhood have been reported [4, 5]. Among these patients, the primary sites were lymph nodes with or without extranodal involvement, and the genetic detection was not performed. We herein report a case of this rare lymphoma with novel STAT5B variants, multiple subcutaneous masses as initial symptom without lymph node involvement in a 9-year-old patient.

PTCL-NOS is the most common type of mature T-cell lymphoma in Western countries, and it is also the second most common mature T-cell lymphoma in China which is accounting for 13.2% of the patients [6]. In addition, this kind of lymphoma is always in adults but very rare in children. Scattered cohorts with a few cases have been reported in pediatric patients. A SNOMED search of the West China Hospital surgical pathology database from January 2014 to October 2017 identified 271 PTCL-NOS patients, whereas only 2 cases (0.7%, including this case) were detected in pediatric group (under the age of 14) during this period. Additionally, 14 of the 271 patients (5.1%) were measured as EBV + PTCL while only this case did not present with lymphadenopathy.

EBV + PTCL, as a variant of PTCL-NOS, is a rare malignancy which is more frequent in the late adulthood with high clinical stage and aggressive clinical course [2]. however, for the patients of childhood, it was extremely rare with limited cases have been reported (Additional file 4: Table S1) [4, 5, 7]. For these cases, lymph node involvement was the significant feature with the common site of cervical region. However, a few extranodal organs may also be involved, with lymphoma presenting in bone marrow and spleen [6]. Typically, the morphology of PTCL-NOS appears a mixture of small to large atypical lymphocytes, with clear cytoplasm, irregular nucleus and obvious nucleoli, invading micrangium and normal lymph node structure, but EBV + PTCL shows different cytomorphology—more commonly centroblastoid, often anaplastic, or plasmacytoid [8]. For the immunophenotype, PTCL usually loss the pan T-cell antigens, such as CD2, CD5, or CD7, of which, CD2 is the most stable T-cell marker. Moreover, most cases of EBV + PTCL are CD8+/CD4-, while double negative or CD4+/CD8- cases are less common, each accounting for about 15% of the cases [2]. Besides, cytotoxic molecule including GranzymeB and TIA-1 are expressed on nearly all of the cases (97%) [2]. In our study, the cytomorphology and phenotypes of the neoplasm conformed to EBV + PTCL with CD2+, CD3p+, CD8+, Granzyme B+, TIA-1+, CD4-, CD5-, CD7- centroblastoid neoplastic cells, nevertheless, the young age at onset, multiple subcutaneous masses without lymph node involvement and good general condition of the patient are different.

The immunophenotype of our young patient with CD3ε+, TIA-1+, GB+ and the positive EBER-ISH could raise the consideration of systemic EBV-positive T cell lymphoma of childhood. Moreover, a Korean study reported that chronic active EBV infection and systemic EBV-positive T cell lymphoma of childhood were the most common type of EBV-associated lymphoproliferative disorder among Asian teenagers [3]. Morphologically, these diseases appear to be polymorphic or monomorphic without obvious pleomorphism of infiltrated cells [9]. Besides, these patients always have a history of initial or chronic EBV infection and present with fever, lymphadenopathy, pancytopenia, progressive hepatosplenomegaly, multiorgan failure, more frequently developing to hemophagocytic lymphohistocytosis (HLH) [1]. However, the morphology and clinical features of our patient did not conform to such disease entitled systemic EBV+ T-cell lymphoma of childhood.

Extranodal NK/T cell lymphoma(ENKTL) should be taken into consideration as one of the differential diagnosis because they share many similarities in extranodal involvements, EBV association and immunophenotypes. Moreover, ENKTL occupies the largest proportion of mature T/NK cell lymphomas in western China [6]. ENKTL with cutaneous involvement or primary cutaneous ENKTL demonstrate atypical small to medium-sized lymphocytes with NK cell phenotype infiltrating into corium and extending into the subcutis, commonly with zonal necrosis. Therefore, ulcer and violaceous plaques are always presented on the skin [10]. Unlike this condition, in our case, the tumour was restricted to subcutaneous tissue without corium infiltration and necrosis. Besides, the tumour was originated from T cell linage, which was also different from ENKTL. Although previous studies reported that some ENKTL cases express TCR and were regarded as T-cell origin, it was rare and only accounted 11% of the cases in a recent study [11], however, most of the ENKTL of T-cell type are originated from γδT cells which rarely express CD8. The differences in systemic EBV + T-cell lymphoma of childhood, ENKTL and our case were summarized in Additional file 5: Table S2).

STAT5B gene consists of 19 exons with 77.23 kilobases (kb) span, located on chromosome 17q11.2. It encodes a slightly smaller peptide of 787 amino acid residues with 6 protein domains, N-terminal domain(ND), Coiled-coiled domain(CCD), DNA binding domain(DBD), Linker(L), Src-homology 2(SH2), Transactivation domain(TAD). STAT5B has been demonstrated to have strong correlation to growth by regulating growth hormone -insulin-like growth factor − 1 (GH-IGF-1) axis via activating IGF-1 expression [12]. A previous study reviewed 10 patients of growth failure due to STAT5B mutations indicated that severe growth failure, marked IGF-1 deficiency and insensitivity to GH are the essential clinical features [13]. This patient was at the height of 110 cm(<-3SDS) [14] with low IGF-1 in serum(<-2SDS) [15] and growth hormone insensitivity (growing 2 cm after 6-month growth hormone therapy, much lower than normal therapeutic response) that might arise our consideration of the abnormality of STAT5B signaling pathway. Moreover, the mutation of STAT5B has been detected in many malignancies, especially in γδ-T-cell lymphoma [16]. In a recent study, STAT5B has been measured in 51 ENKTL cases, to find 1 case of N642H and 2 cases of Y665F mutations [16]. However, no studies focus on STAT5B mutation in systemic EBV + T-cell lymphoma of childhood and PTCL-NOS was published. The mutation, N642H in Src-homology 2 (SH2) domain, was demonstrated to associate with increased phosphorylated protein and high proliferative activity of the tumor cells [16]. Accordingly, STAT5B sequencing was applied for this patient in both neoplastic tissue and peripheral blood sample. Interestingly, two variants which have not been reported, S420Y in DNA binding domain and E623K in SH2 domain, were detected in neoplastic tissue, however, such variants were not detected in blood sample. This result indicated that growth retardation of this patient was not caused by STAT5B signaling pathway dysfunction, but the variants of STAT5B (especially E623K in SH2 domain) in neoplastic tissue might contribute to the tumor proliferation. To the best of our knowledge, no researches investigated the STAT5B variant in PTCL-NOS. Our study may serve as a modest spur to induce someone to come forward with his valuable contributions.

Comparing to other EBV + PTCL, our patient showed different characteristics. EBV + PTCL is always associated with poor prognosis with the median survival of 4 months due to the drug résistance. However, our patient responded well and achieved complete remission after chemotherapy. Interestingly, this patient suffered relapse twice within 8 months.