Coincidence of de novo T-lymphoblastic lymphoma and cutaneous gamma/delta peripheral T-cell lymphoma

Abstract

The coincidence of acute T-lymphoblastic leukemia/lymphoma, NOS (T-ALL/LBL), and peripheral T-cell lymphoma (PTCL) is unusual, and there have only been a few cases of their metachronous occurrence. In these cases, PTCLs emerged as recurrence after primary therapy for primary T-ALL, were the rare gamma/delta type, and uncommonly involved skin for T-ALL/LBL. We herein report the first case of de novo T-LBL that coincided with cutaneous gamma/delta PTCL before primary therapy. A 70-year-old man presented with systemic lymphadenopathy. Lymph node biopsy revealed a massive proliferation of lymphoblastoid cells; immunohistochemically, they were positive for TdT/CD1a/CD99, and cytoplasmic CD3ε, CD4, and CD8 and were negative for T-cell receptor (TCR) βf-1. A few TCRδ-positive cells were intermingled. Atypically, TIA was focally positive, whereas granzyme/perforin was negative. Multiple papules and plaques emerged on the trunk before the initiation of treatment for T-LBL. Skin biopsy revealed a massive proliferation of medium-to-large atypical lymphoid cells that were TdT/CD1a-negative mature T-cells; they were negative for TCRβf1 and CD4, and positive for TCRδ, CD5, CD8, CD56, TIA, granzyme B, and perforin. A conventional PCR analysis of TCRG showed no identical clonal band between the two tumors. The skin lesion was diagnosed as cutaneous gamma/delta T-cell lymphoma. Whether the lesion was primary or a transformation of T-LBL was unclear. After treating with reduced hyper-CVAD/MA targeting T-LBL, molecular complete remission was achieved. When an uncommon cutaneous lesion emerges in the course of T-ALL/LBL, both need to be evaluated pathologically and genetically, whether de novo or recurrent, assuming the possibility of coincident gamma/delta PTCL.

INTRODUCTION

T-lymphoblastic lymphoma (T-LBL) derives from precursor T-cells, the same as T-lymphoblastic leukemia (T-ALL). Nevertheless, its primary involvement is the lymph nodes, thymus, or an extranodal site, with less than 20% of cases involving peripheral blood and/or the bone marrow by definition.¹ There have been a few cases of the metachronous onset of immature T-ALL (T-ALL/LBL, NOS) and mature peripheral T-cell lymphoma (PTCL);² PTCLs were all recurrent cases after primary therapy for T-ALL. Furthermore, they were all rare gamma/delta type PTCL and involved the skin, which is uncommon for T-LBL.^3,4 In one case, clonality in T-cell receptor B (TCRB), and G (TCRG) was confirmed between T-ALL and PTCL cells with PCR analyses. We herein report the first de novo case of T-LBL (T-ALL/LBL) that occurred simultaneously with cutaneous gamma/delta PTCL involving the trunk diffusely before the initiation of primary therapy for T-LBL.

Case presentation

A 70-year-old man was referred for tonsil enlargement. Performance status was 1 without B symptoms. Computed tomography (CT) revealed systemic lymphadenopathy and fluorine-18 fluorodeoxyglucose positron emission tomography/CT (FDG-PET CT) showed abnormal uptake from the cervical lymph nodes to bilateral iliac nodes (Fig. 1A). No involvement was detected in peripheral blood (white blood cell count, 4,910/ml) or bone marrow. The level of the soluble IL-2 receptor was elevated (866 U/mL), while that of lactase dehydrogenase was within normal limits (152 U/L). The levels of liver enzymes were also high (AST 175 IU/L, ALT 85 IU/L, ALP 482 IU/L, and γ-GTP 502 IU/L), suggesting liver involvement. Plate count was normal (16.2×10⁴/µL), but coagulation markers were abnormal (Fibrinogen 65 mg/dl, PT% 43, FDP 22.3 µg/ml, Antithrombin III 69%). Concurrent disseminated intravascular coagulation was suspected. A cervical lymph node biopsy was performed. Multiple papules and plaques appeared in the trunk soon after lymph node biopsy (Fig. 1B), and a skin lesion was also biopsied to confirm the skin involvement of T-LBL cells.

Fig. 1.

FDG-PET CT showing abnormal uptake from systemic lymph nodes (arrows). A Upper; cervical, axillary lymph nodes, lower; left inguinal, bilateral iliac lymph nodes. B Image of multiple papules and plaques that emerged on the back.

Pathological and flow cytometric findings of cervical lymph nodes

Cervical node excisional biopsy showed diffuse infiltration of medium-sized, atypical lymphoblastoid cells, with few remnants of atrophic lymph follicles. Tumor cells were mostly uniform in size, but with a slightly irregular morphology and vesicular chromatin (Fig. 2A, B). Immunohistochemically, blastoid cells were positive for TdT (Fig. 2C), CD1a, CD99, CD2, CD3, CD5, CD7, and CD10 and partially positive for CD4 (Fig. 2D) and CD8 (Fig. 2E). Although these findings suggested that tumor cells were immature T-blastic cells, they were partially positive for TIA (Fig. 2F). Cells were negative for granzyme B and perforin, as well as CD56 and TCRβf1. A few TCRδ-positive cells were observed (Fig. 2G). CD79a showed weak, membranous atypical expression (Fig. 2H), while PAX-5 and CD20 were negative. CD34 and CD117 were also negative. EBER-ISH was negative. A flow cytometric analysis of tumor cells (Fig. 2I. outsourced to SRL, Tokyo, Japan) showed positivity for TdT (although the positive rate was low compared with that of immunohistochemistry), CD2, CD5, CD7, CD10, CD4, and CD8, and negativity for surface CD3ε, CD19, and CD20, consistent with immunohistochemical findings. CD8 and CD4 positive components were detected, respectively. A few TCR γδ cells were also detected, but the number was too small to decide whether they were PTCL cells, described below, or not. A G-banding analysis failed due to poor proliferation. Considering the progressive clinical course and pathological findings, the patient was diagnosed with T-LBL (T-ALL/LBL, NOS).

Fig. 2.

Pathological findings of cervical lymph nodes. A, B Hematoxylin and eosin staining of an enlarged lymph node. Few atrophic lymphoid follicles are observed. The uniform infiltration of middle-sized atypical lymphoid cells with slightly irregular nuclei is noted. Immunohistochemically, tumor cells are positive for TdT (C), CD4 (D), CD8 (E), and TIA (partially, F). Most tumor cells are negative for TCRδ; however, a few scattered small-to-large positive cells are also present (G). The tumor cells demonstrated atypical membranous expression of CD79a (H). Dot plots of flowcytometric analysis (I). In most tumor cells, proliferating cells were surface CD3 negative, cytoplasmic CD2, CD5, and CD7-positive, and TCRαβ and TCRγδ-negative. There were more CD8-positive cells than CD4-positive cells. TdT was positive, but its positive rate was not as high as in immunostaining.

Pathological findings of erythematous lesions (trunk)

A histological examination revealed medium-to-large atypical lymphoid cells with anisocytosis, and a rich cytoplasm infiltrated the dermis to the subcutaneous region (Fig. 3A, B). The subepidermal area was highly edematous; under a low-power field, the Grenz zone appeared to be present in a large area, whereas cutaneous invasion was detected focally in a high-power field (Fig. 3C). Immunohistochemically, tumor cells were negative for TdT (Fig. 3D), CD1a, and CD99, and positive for CD3 and CD5 (weak). CD4-positive cells were mostly non-tumor histiocytes (Fig. 3E), and the majority of tumor cells were positive for CD8 (Fig. 3F). They were also positive for CD56 (weak), TIA, and granzyme B (Fig. 3G) as well as perforin and TCRδ (Fig. 3H). CD2, CD7, CD10, and TCRβf1 were all negative. EBER-ISH was negative. Morphologically and immunohistochemically, tumor cells were not immature T-LBL cells but mature/peripheral T-cell lymphoma cells. Flow cytometric and G-banding analyses were not performed.

Fig. 3.

Pathological findings of the skin. A, B Hematoxylin and eosin staining shows atypical lymphoid cells with anisokaryosis and a rich cytoplasm mainly infiltrating the dermis. The Grenz zone is mostly preserved under a low-power field; however, the infiltration of some tumor cells into the epithelium (C) is observed in the high-power field. Tumor cells are negative for TdT (D). Most cells are negative for CD4. Weakly-positive cells are considered to be histiocytes (E), but are positive for CD8 (F), granzyme B (G), and TCRδ (H).

Conventional Biomed 2-based TCRG PCR analysis (Figure 4)

Fig. 4.

Conventional Biomed 2 -based PCR clonality analysis of TCRG (left; tube A, right; tube B) Tube A detects major clonal peaks, and Tube B detects minor clonal peaks. Electrophoresis demonstrates that T-LBL shows a few bands with smears in TCRG tubes A and B; γδ-type PTCL shows biclonal bands in TCRG tube A. No identical bands are detected in both tumors. NC: negative control, PC: positive control.

Fresh tissues of the two tumors were not available for analysis. Following the manufacturer’s instructions, DNA was extracted from each tumor’s formalin-fixed paraffin-embedded (FFPE) tissue using the TaKaRa DEXPAT Easy DNA kit (Takara Bio Inc, Shiga, Japan). Based on the Biomed 2 protocol, conventional PCR for TCRG (tubes A and B) was performed with heteroduplex analysis.⁵ Electrophoresis of PCR products showed that T-LBL had a few indecisive bands with smears, whereas cutaneous PTCL showed two clear bands at approximately 200–250 bp in TCRG tube A, indicating clonality. No definitive common, identical bands were detected in either tumor (Fig. 4).

Clinical course

Neither tumor invaded the bone marrow. Although the traits and morphology of tumor cells in the two lesions were discordant, treatment mainly targeting T-LBL with a reduced dose of a hyper-CVAD/MA regimen was initiated, which stopped the progression of and improved both lesions in the middle of chemotherapy. After four courses of therapy, FDG-PET CT showed no residual lesions systemically.

DISCUSSION

The present case demonstrated that a de novo T-LBL (T-ALL/LBL, NOS) lesion may occur simultaneously with a PTCL lesion. The admixture of the two tumor components was not evident in each lesion. Furthermore, by coincidence, PTCL cells may be the TCR gamma/delta type and involve the skin, which is uncommon for T-ALL/T-LBL.^4,6

Two cases of their metachronous occurrence have previously been reported, in which transformation from T-ALL (T-ALL/LBL, NOS) to PTCL was suggested.² These cases shared the following common features: PTCL occurred after primary therapy for T-ALL with approximately four-month and four-year intervals, was the γδ type, and involved the skin. Genetically, at least one case showed identical clonal TCR rearrangement peaks for both TCRβ and TCRγ by conventional PCR (the materials by which DNA was extracted were not described).

Differences between the present case and the reported cases above other than simultaneous or metachronous occurrence were as follows: 1) the lymphoblastic lesion was T-LBL with no peripheral or bone marrow involvement in the present case, and 2) clonality was unclear in the present case. Regarding the first point, recent studies reported a difference in gene expression between the two; however, a consensus has not been reached.⁷ Concerning the second point, analytical methods were limited, particularly in the present case; therefore, whether each tumor is a novel lesion or a transformed one requires further genetic investigation.

The reason why coincident PTCL was the rare γδ type is unknown. Previous studies have reported γδ-type T-cells in 0.5–10% of total circulating lymphocytes,⁸ accounting for 1–5% of T-cells⁹ and less than 1% of all lymphoid neoplasms.¹⁰ Mature γδ-type T-cell lymphomas, such as hepatosplenic T-cell lymphoma and enteropathy-associated T-cell lymphoma, are rare, with a reported incidence ranging between 1.2 and 4.2% of all T-cell lymphomas.¹¹ However, in contrast to their rarity, the fate of γδ cells in T-cell differentiation is decided prior to αβ cells; the selection of γδ cells occurs first, and only if this is unsuccessful are the αβ fate and αβ lineage adopted.¹² Therefore, γδ-type T-cells are closer to precursor cells than αβ-type T-cells at the differentiation level. However, the origin or normal counterpart of T-ALL/LBL, NOS cells, has not yet been defined;¹ therefore, further clarification is necessary.

The differential diagnosis of T-LBL in the present case may include Indolent T-lymphoblastic proliferation (IT-LBP), a new etiology listed in the WHO classification 5th edition.^13–15 IT-LBP typically exhibits an indolent, long clinical course. Histopathologically, the cells lack atypia and preserve tissue architecture. In contrast to IT-LBP, T-LBL frequently shows aberrant antigen expression (such as CD34, CD33, CD79a) and/or the loss of the usual T markers, as well as positivity for LMO2. The LMO2 antibody was unavailable in the present case, but the clinical course was progressive. Furthermore, proliferating cells destroyed the normal architecture of the node and demonstrated atypia with aberrant immunohistochemical expression of CD79a and loss of surface CD3ε in flowcytometry. Taken together, we consider that the present case was compatible with T-LBL.

In conclusion, a re-examination with precise pathological and genetic investigation is desirable when cutaneous lesions appear with T-lymphoblastic lesions, whether de novo or recurrent, and T-LBL or T-ALL, as the tumor may be PTCL.