Angioimmunoblastic T-cell lymphoma harboring a t(8;14)(q24;q11.2)/TCR::MYC translocation that presented with intestinal infiltration

doi:10.21203/rs.3.rs-4978464/v1

Although rearrangement of the MYC oncogene (MYC-R) is frequently observed in aggressive B-cell lymphomas, it is extremely rare in T-cell malignancies. A 64-year-old man who had been under observation for several years because of asymptomatic pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue(MALToma) was admitted to our hospital because of poor general condition and hypotension. Blood tests revealed thrombocytopenia and elevated serum lactate dehydrogenase levels, whereas computed tomography revealed systemic lymphadenopathy and splenomegaly. An inguinal lymph node biopsy precipitated a diagnosis of angioimmunoblastic T-cell lymphoma (AITL). Shortly after admission, the patient experienced spontaneous intestinal perforation and hemorrhage caused by multiple intestinal infiltrations of the AITL. Although chemotherapy was administered, the patient died several weeks after admission. A 46,XY,t(8;14)(q24;q11.2) karyotype was identified, and fluorescence in situ hybridization analyses showed split signals for the MYC and T-cell receptor (TCR) alpha genes, by which a TCR::MYC translocation was confirmed. Pathological autopsy analysis revealed systemic infiltration of the AITL and no MALToma lesions. Only a few cases of mature T-cell lymphoma harboring MYC-R have been reported in the literature thus far. To the best of our knowledge, this is the first reported case of AITL with TCR::MYC rearrangement. This condition could be associated with refractoriness to chemotherapy and aggressive clinical course with systemic infiltrationthat included the intestine.

The MYC oncogene (also known as c-MYC) is commonly activated in various human malignancies, as it can promote neoplastic growth through various mechanisms. MYC rearrangement (MYC-R) is frequently observed in aggressive B-cell lymphomas such as Burkitt lymphoma and diffuse large B-cell lymphoma, and is associated with aggressive clinical behavior and a poor prognosis. However, the clinicopathological significance of MYC activation in T-cell malignancies remains unclear. Thus far, MYC-R in mature T-cell neoplasms is considered extremely rare, and TCR::MYC translocation has only been reported in some cases of T-lymphoblastic leukemia or lymphoma [1–3]. To the best of our knowledge, this is the first reported case of angioimmunoblastic T-cell lymphoma (AITL) with MYC-R.

A 64-year-old man who had been suffering from general fatigue and anorexia for one month was admitted to our hospital because of a poor general condition. He had been diagnosed with extranodal marginal zone lymphoma with mucosa-associated lymphoid tissue (MALToma) of the stomach 23 years prior, which resolved after Helicobacter pylori eradication and radiotherapy. MALToma had developed again in the patient’s lung 7 years prior, for which no therapeutic intervention was performed because the lesion had been asymptomatic and stable in size. On admission, he was alert and afebrile, but critically ill with hypotension. Complete blood testing revealed mild leukopenia (3,000/µL, with 82% neutrophil, 1% basophil, 12% lymphocyte, 4% monocyte, and 1% atypical lymphocyte) and thrombocytopenia (74,000/µL). Coagulation tests revealed elevated levels of fibrin degenerative product (18.4 µg/dL) and D-dimer (14.9 µg/dL), without decrease in fibrinogen level (204 mg/dL). Biochemical data showed elevated lactate dehydrogenase (LDH; 584 IU/L) and soluble interleukin-2 receptor (10,247 U/mL) levels, as well as mild liver dysfunction. Renal insufficiency (urea nitrogen 47 mg/dL and creatinine 2.03 mg/dL) and hypoalbuminemia (2.90 g/dL) were also observed, and considered likely to have been caused by dehydration and malnutrition since the patient could not eat or drink well immediately preceding his admission. The patient’s C-reactive protein (3.85 mg/dL) and ferritin (1,555 ng/mL) levels were mildly elevated. His plasma level of Epstein-Barr viral DNA was elevated (1.7 × 10⁴copies/µg DNA). Computed tomography (CT) showed systemic lymphadenopathy and splenomegaly. A biopsy of his inguinal lymph nodes was performed on the second day of his admission, which revealed the proliferation of abnormal pale and clear cells with irregularly shaped nuclei, under the background of infiltration of inflammatory cells and venules (Fig. 1a). The abnormal cells were immunophenotypically CD2⁺, CD3⁺, CD4⁺, CD5⁺, CD7^–, CD8^–, ICOS⁺, and PD-1⁺ (Fig. 1b–f). Tests for cytotoxic molecules such as TIA-1 and granzyme B were negative. In situ hybridization for Epstein-Barr virus-encoded RNA was positive in only a few of the smaller lymphocytes (Fig. 1g). The patient’s Ki-67 labeling index was ~ 70%. Rearrangement of the T-cell receptor gene at the Cβ1 locus was demonstrated via Southern blotting, whereas that of the immunoglobin heavy chain joining region (J_H) was negative. Based on these findings, a diagnosis of AITL was made.

On the patient’s fourth day of admission, he suddenly experienced severe abdominal pain caused by a small intestinal perforation, which required emergency surgery. The resected intestinal specimen showed multiple infiltrations of abnormal T cells that were phenotypically identical to the lymphoma cells in the lymph nodes (Fig. 2). Bone marrow examination also revealed infiltration of the lymphoma cells (Fig. 3a). One week after surgery, the patient experienced a massive intestinal hemorrhage, for which endoscopic procedures barely resulted in hemostasis. He received chemotherapy with an etoposide, prednisolone, cyclophosphamide, and doxorubicin (EP(O)CH regimen; omitting vincristine) beginning one week after the hemorrhage. Slight regression of the lymphadenopathies was observed via CT after three weeks of this treatment. However, over the next several days, rapid progression of the disease was observed, with severe coagulopathy resulting in intracranial hemorrhage. Shortly thereafter, the patient died. A pathological autopsy revealed infiltration of his AITL into the liver, spleen, kidneys, heart, right lung, small intestine, colon, and multiple lymph nodes (Supplementary Fig. 1). B-cell lymphoma lesions were not detected in any of the organs.

G-banding analysis of the bone marrow showed a karyotype of t(8;14)(q24;q11.2) in 12 of the 16 analyzed cells (Fig. 3b), which was also observed in an analysis of lymph nodes cell. Fluorescence in situ hybridization for the MYC (located on 8q24) and T-cell receptor alpha (TCRa; located on 14q11.2) genes revealed split signals for both (Fig. 3c,d). These findings confirmed TCR::MYC translocation.

The clinicopathological significance of MYC expression in peripheral T-cell lymphomas, including AITL, has yet to be established—although some investigations concerning this issue have been reported in the literature. Manso et al. analyzed C-MYC, GATA3, and Ki-67 expression in PTCLs (n=128, including 74 AITL cases and 54 cases of PTCL, not otherwise specified) using immunohistochemistry (IHC) and reported a significant correlation between positive C-MYC expression (>20% positivity) and high Ki-67 labeling index (>80%) [4]. C-MYC was positive in 13.3% of the cases, and its presence correlated with a poor prognosis among AITL cases. In another study, Peng et al. analyzed C-MYC statuses using IHC and FISH in 44 AITL cases. Those with positive C-MYC expression (defined as >5%; n=29) had lower survival rates than their negative counterparts, and monoclonal B-cell expansion was frequently observed in the C-MYC-positive population [5]. MYC amplification was detected in several cases, but its translocation was not observed. Considering these findings, positive MYC expression in AITL may be associated with an aggressive clinical course and poor prognosis, which should be confirmed in larger trials.

MYC rearrangements in PTCL are extremely rare. Only a few PTCL cases harboring MYC rearrangements have been reported in the literature thus far. Their clinicopathological features, alongside those of the present case, are listed in Table 1 [6-11]. Among them, anaplastic large cell lymphoma (ALCL) is the most common histological type. Many of these appear to be accompanied by systemic lesions and B symptoms. Although ALCL, particularly if ALK-positive, typically has favorable chemosensitivity and a good prognosis, most ALCL cases with MYC rearrangement seem to be refractory to chemotherapy and result in early death. Consistent with these findings, our patient presented with systemic lesions, was refractory to chemotherapy, and experienced premature death. These aggressive clinical aspects may be associated with consistent activation of the MYC oncogene [12].

Although patients with AITL typically present with systemic extranodal lesions in regions such as the skin, liver, spleen, and bone marrow [13], intestinal AITL infiltration is considered extremely rare. Postmortem pathological investigations in previous cases of angioimmunoblastic lymphoid dysplasia (AILD), most of which would have been diagnosed as AITL using present-day criteria, did not reveal intestinal infiltration of lymphoma cells [14-17]. Some reported cases of AILD in which intestinal infiltration was pathologically demonstrated also showed disseminated lymphoma lesions [18, 19]. One patient presented with abdominal pain and diarrhea, was diagnosed via biopsies of the ileocecum and lymph nodes, and died 10 months after his diagnosis, without chemotherapeutic intervention [20]. That case was unique among a larger report of 27 cases of intestinal NK/T-cell lymphomas at a single institute. The present case is considered a unique case of AITL complicated by spontaneous intestinal perforation and fatal intestinal bleeding caused by AITL infiltration into the intestinal wall, accompanied by systemic infiltration into various other organs as well. These features may be associated with TCR::MYC translocation, considering the aggressive clinical behavior of MYC-associated lymphoma—irrespective of the histological subtype.

In summary, we herein described a case of AITL harboring TCR::MYC that presented with intestinal infiltration. To the best of our knowledge, this is the first case report of AITL harboring a TCR::MYC translocation, which was clinically characterized by intestinal infiltration, refractoriness to chemotherapy, and an aggressive clinical course. Further experiences with this disease etiology are required to elucidate the clinicopathological features of AITL with MYC rearrangements.

Funding

No funding was provided for this study.

Ethical approval
Patient identifiers have been redacted. Written informed consent was obtained from the patient.

Conflicts of interest

The authors declare no conflicts of interest relevant to this study.

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Table 1. Reported peripheral T-cell lymphoma cases harboring MYC rearrangement

Refer-ences	Histological subtypes	Age/sex	Lesion sites	B symp-toms	Cytogenetic findings	Therapy	HSCT (donor)	Outcome
[6]	ALCL, ALK(+)	13/M	LN, peripheral blood	NA	NPM::ALK, MYC[R]	CHOP-like, COPADM1	Yes (HLA-identical sibling)	DOD (<6 months from presentation)
[7]	ALCL, ALK(+)	11/F	LN, thyroid, skin	Yes	NPM::ALK, ALO17::MYC	ALCL99	No	DOD (7 months from diagnosis)
[8]	ALCL, ALK(+)	9/M	Bone, intra-abdominal, adrenal, paratracheal, small intestine	Yes	NPM::ALK，MYC[R]	ANHL0131, CCG-0894	Yes (cord blood)	Alive without disease (>18 months from HSCT)
[9]	ALCL, ALK(+)	28/M	LN	No	ALK[R], MYC[R]	CHOP	No	Alive without disease (58 months from diagnosis)
[10]	ALCL, ALK(–)	58/F	LN	Yes	MYC[R]	CHOP, ESHAP	No	DOD (9 months from diagnosis)
[10]	ALCL, ALK(–)	63/M	LN	No	MYC[R], DUSP22[R]	BV	Yes (autologous)	Died of unknown cause (53 months from diagnosis)
[11]	EATL	66/F	Small intestine	Yes	MYC[R]	NA*	Yes (autologous)	Alive without disease (6 months from operation)
Present case	AITL	64/M	LN, intestine, bone marrow	No	TCR::MYC	EPOCH	No	DOD (1.5 months from diagnosis)

Abbreviations: ALCL, anaplastic large cell lymphoma; DOD, died of disease; EATL, enteropathy-associated T-cell lymphoma; F, female; HSCT, hematopoietic stem cell transplantation; LN, lymph node; M, male; NA, not available.

No competing interests reported.

TCRMYCAITLSupplFigs01.pptx
Supplementary Figure 1: Pathological autopsy findings. Hematoxylin-Eosin staining of the liver (a, ×5; b, ×20), spleen (c, ×5; d, ×20), kidney (e, ×5; f, ×20), adrenal gland (g, ×5; h, ×20), small intestine (i, ×5; j, ×20), large intestine (k, ×5; l, ×20), heart (m, ×5; n, ×20), and lungs (o, ×5; p, ×20) showing lymphoma cell infiltration in all tissues. The abnormal cells in the pulmonary lesion were immunohistochemically CD3⁺ (q), CD4⁺ (r), and CD20^– (s), which suggests a T-cell lineage and excludes the possibility of MALT lymphoma.

Angioimmunoblastic T-cell lymphoma harboring a t(8;14)(q24;q11.2)/TCR::MYC translocation that presented with intestinal infiltration

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