The Power of Hematopoietic Stem Cell Transplantation (HSCT): A Curative Approach for Diffuse Large B‐Cell Lymphoma (DLBCL) Incidentally Detected in a SCID Baby

ABSTRACT

Lymphoma is a rare complication of X‐linked severe combined immunodeficiency (X‐SCID) caused by IL2RG deficiency. We report an infant with IL2RG‐SCID who developed diffuse large B‐cell lymphoma (DLBCL) during pretransplant evaluation. A male infant with T−B+ SCID was diagnosed at 1 month of age and referred for hematopoietic stem cell transplantation (HSCT). Pretransplant imaging unexpectedly revealed a thoracic mass, and biopsy confirmed EBV‐negative DLBCL. Rituximab and low‐dose chemotherapy failed to reduce the mass and were complicated by severe infections. The patient subsequently underwent unconditioned haploidentical HSCT with posttransplant cyclophosphamide. Full donor T‐cell chimerism was achieved by Month 3, and complete resolution of the lymphoma was observed 15 months after HSCT. Successful HSCT and immune reconstitution may achieve lymphoma control in IL2RG‐SCID when conventional chemotherapy is poorly tolerated.

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1. Introduction

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of disorders characterized by impaired T‐cell development and severe cellular and humoral immunodeficiency. X‐linked SCID (X‐SCID) is the most common form of SCID and is caused by mutations in the gene encoding the common γ chain (γc) shared by the receptors for IL‐2, IL‐4, IL‐7, IL‐9, and IL‐15 [1, 2]. Deficiency of the IL2RG chain leads to profound impairment of T‐ and natural killer (NK)‐cell development, whereas B‐cell numbers are usually normal or increased but functionally impaired [3].

Patients with IL2RG deficiency typically present with severe respiratory and gastrointestinal infections, opportunistic infections, candidiasis, and growth failure. Lymphoproliferative disease (LPD) is not a typical early manifestation, and lymphoma is rarely reported in patients with IL2RG deficiency. Management is particularly challenging because severe infections may preclude conventional chemotherapy, while active malignancy complicates the timing and approach to hematopoietic stem cell transplantation (HSCT) [4].

Here, we report an infant with SCID due to IL2RG deficiency in whom EBV‐negative diffuse large B‐cell lymphoma (DLBCL) was unexpectedly detected during pretransplant evaluation and subsequently completely regressed following unconditioned haploidentical HSCT.

2. Case Presentation

A baby boy born at 38 weeks of gestation, weighing 3010 g, was admitted to a private hospital with vomiting and diarrhea at 1 month of age. Entamoeba histolytica cysts were detected in the stool, and the patient was hospitalized and treated intravenously. However, due to persistent symptoms, he was referred to another center where a milk elimination diet was recommended to the mother with a diagnosis of cow's milk protein allergy. Since his symptoms did not improve, he was referred to a pediatric immunology clinic, where a diagnosis of T−B+ SCID was established based on lymphopenia (total lymphocyte count, 1120/mm³), hypogammaglobulinemia (IgG 213 mg/dL [376–685], IgA < 6 mg/dL [9–30], IgM 39.5 mg/dL [36–77]) [5], and markedly abnormal peripheral blood lymphocyte subsets (Table 1). At 2 months of age, he was referred to our department for HSCT.

TABLE 1.

Immunological evaluation at diagnosis and following HSCT.

	Diagnosis	+1 MO Post HSCT	+2 MO Post HSCT	+6 MO Post HSCT	+12 MO Post HSCT	+24 MO Post HSCT
WBC (mm3) (6000–17,000)	8870	5410	3460	9560	8410	12,250
ANC (mm3) (1500–8000)	5410	1860	830	2510	1750	3370
ALC (mm3) (3000–10,000)	1780	2510	2000	6100	5870	8060
Hb (g/dL) (10.5–14)	14.5	11.6	9.4	12.0	12.8	12.1
PLT (mm3) (150,000–450,000)	391,000	309,000	344,000	383,000	262,000	335,000
IgG (mg/dL)	213 (376–685)	—	856 (463–1006)	1110 (605–1430)	1290 (604–1941)	701(604–1941)
IgA (mg/dL)	< 6.6 (9–30)	—	< 24 (17–69)	27 (30–107)	25 (26–296)	23 (26–296)
IgM (mg/dL)	39.5 (33–154)	—	< 19 (46–159)	94 (66–228)	208 (71–235)	56 (71–235)
EBV PCR (IU/mL)	Negative	Negative	Negative	Negative	Negative	Negative
CMV PCR (IU/mL)	74,000	2512	316	158	Negative	Negative
CD3+CD16‐CD56− % (51–79)/mm3	3/29	78/1957	92/1840	70/4270	70/4109	70/5642
CD3‐CD16+CD56+ % (5–23)/ mm3	10/97	12/301	6 /120	10/610	7/410	11/645
CD3+CD4+ % (31–54)/ mm3	1/9.7	61/1531	6/120	21/1280	29/1702	29/1702
CD3+CD8+ % (10–31)/ mm3	0.1/0.9	19 /476	87/1740	45/2745	40/2348	39/2289
CD19+ % (14–44)/ mm3	80/776	0.01/0.25	0.01/0.25	16/976	18/1056	16/939
CD20+ % (13–40)/ mm3	80/776	0.01 /0.25	0.01/0.25	16/976	18/1056	16/939
TCR ɣ/δ %	5	0.01	1	7	3	3
CD4+CD45RO+ % (6–21)/ mm3	4/38	71/182	4/80	7/427	10/587	7/410
CD4+CD45RA+ % (25–45)/ mm3	3/29	1/25	3/60	14/854	24/1408	22/1291
RTE(CD4+CD45RA+CD31+)	0 (50–100)	1 (61–93)	1 (61–93)	62 (40–100)	73 (40–100)	63 (37–100)
Activation responses to PHA CD3+CD25+ % (52.4–93.7) CD3+CD69+ % (47.9–84.8) CD4+CD25+ % CD4+CD25+ %			49 51 13 12	67 67 41 41	79 78 47 46	71 68 34 35
B cell subsets CD19 + IgM − 27 + IgD − (Switched Memory B)% CD19 + IgM + 27 + IgD + (Marginal Zone B)% CD19 + IgM+27 − IgD + (Naive B)% CD19 + CD38LowCD21Low (Aktive B)%	—	—	—	—	1.4 (3.9–13.6) 5.7 (4.1–13.9) 83.2 (68.1–89.3) 5.7 (1.0–5.7)	1.6 (4.7–21.2) 3.7 (2.7–19.8) 90.4 (54.0–88.4) 0.8 (1.7–5.4)
T Cell chimerism%	—	88	91	95	96	95
B Cell chimerism%				23

Family history revealed that the patient's maternal uncle had been diagnosed with IL2RG deficiency due to the same pathogenic IL2RG variant identified in the patient, had undergone HSCT 30 years earlier, and remained alive and well (Figure 1).

FIGURE 1.

Pedigree of the patient's family (E.G.: Current patient; *Haploidentical donor [father] of the current patient [E.G.]; **maternal uncle who had been transplanted).

Physical examination revealed no pathological abnormalities, with good general health, growth, and development. Laboratory evaluation demonstrated marked lymphopenia, hypogammaglobulinemia, and CMV PCR positivity. Further immunological evaluation showed CD3+CD16−56+: 3% (51–79), CD3+CD4+: 1% (31–54), CD3+CD8+: 0.1% (10–31), CD19+: 80% (14–44), CD20+: 80% (13–43), and recent thymic emigrants (RTE): 0% (Table 1). Intravenous immunoglobulin (IVIG), trimethoprim‐sulfamethoxazole, acyclovir, and fluconazole prophylaxis were initiated. Ganciclovir treatment was started because of a high CMV PCR level (74,000 IU/mL).

During pretransplant evaluation, a 1 × 1 cm hypoechoic mass was detected in the left hepatic lobe by abdominal ultrasonography. Because an infectious focus was initially suspected, intravenous antibacterial and antifungal treatment was started. Thoracic CT subsequently revealed an 8‐mm extrapulmonary soft‐tissue lesion in the right paravertebral region between the seventh and eighth intercostal spaces. MRI demonstrated a solid, smoothly contoured, homogeneously enhancing lesion in the right paravertebral‐retropleural region from T5 to T9, extending into the right neural foramina at T6–7 and T7–8 and the epidural space, with partial spinal canal involvement and anterior displacement of the spinal cord (Figure 2).

FIGURE 2.

Contrast‐enhanced spine MRI demonstrates a paravertebral‐retropleural solid lesion extending to the right sided neural foramina and epidural space (arrows).

An open surgical biopsy was performed. Histopathological examination demonstrated diffuse infiltration by large atypical lymphoid cells with strong CD20 expression. The cells were polytypic by light‐chain in situ hybridization and polyclonal by IgH PCR. The infiltrating cells were diffusely BCL2‐positive, with prominent CD30 expression, whereas MUM1, BCL6, and CD10 were negative. The Ki‐67 proliferation index was 50%. EBER in situ hybridization was negative, as was HHV8 (Figure 3). Both tumor tissue and serum were negative for EBV PCR. Based on the overall morphological and immunophenotypic findings, the lesion was diagnosed as DLBCL despite the absence of demonstrable B‐cell clonality.

FIGURE 3.

On H&E sections the infiltrative cells were pleomorphic, medium, and large. These were strong diffusely positive with CD20, and BCL2. Here, 50% of them were expressing CD30. Ki67 proliferation index was around 50%. CD38 revealed increased plasma cells. With CD3, the microenvironment was poorly having T cells. Lambda and Kappa in situ hybridization revealed polytypic IG light chain expression. Molecular clonality results by PCR also revealed a polyclonal B cell population.

Targeted next‐generation sequencing identified a hemizygous splice‐donor variant in IL2RG (Xq13.1), c.854+1G>C (ENST00000374202). This variant affects the canonical + 1 splice site of Intron 7 and is predicted to disrupt normal mRNA splicing, resulting in loss of functional IL2RG common γ‐chain protein.

The patient was diagnosed with IL2RG‐deficient SCID at 2 months of age and DLBCL at 4 months of age. Following multidisciplinary discussion involving pediatric immunology, pediatric oncology, pathology, and radiology, treatment with six doses of rituximab and two cycles of reduced‐dose cyclophosphamide and vincristine was initiated. However, no radiological regression of the mass was observed. Treatment was complicated by CMV reactivation, severe intermittent neutropenia, rotavirus gastroenteritis, COVID‐19 infection, and sepsis, precluding further chemotherapy.

Because the patient could not tolerate additional chemotherapy and no fully HLA‐matched donor was available, paternal haploidentical HSCT was performed without a conditioning regimen. Posttransplant cyclophosphamide was administered at 50 mg/kg/day on Days +3 and +4, with methotrexate and tacrolimus for GvHD prophylaxis. The patient received a bone marrow graft containing 6.14 × 10⁶/kg CD34+ cells. Donor T‐cell chimerism progressively increased after transplantation, reaching 98% by the third posttransplant month, without clinical evidence of GvHD.

The early posttransplant period was complicated by rotavirus infection, CMV reactivation, Streptococcus pneumoniae infection, sepsis, and lower‐extremity lymphedema. EBV PCR remained negative throughout follow‐up. PET‐CT performed 4.5 months after HSCT showed complete disappearance of the previously identified hypermetabolic lesion at the right posterior T6–7 level. Serial thoracic MRI demonstrated progressive regression of the paravertebral mass in parallel with donor T‐cell engraftment. At 24 months after HSCT, no residual soft‐tissue thickening or pathological signal abnormality was detected (Figure 4).

FIGURE 4.

Initial and follow‐up serial contrast‐enhanced T1‐ weighted images reveal the complete regression of the mass over time (arrows). (a) Initial, (b) postoperative imaging, (c) following chemotherapy, (d) follow‐up imaging at 12 months after BMT, (e) follow‐up imaging at 24 months after BMT.

3. Discussion

IL2RG deficiency results in profound T‐ and NK‐cell deficiency and causes X‐SCID. Although LPD is not a typical presenting manifestation in early infancy, lymphoma has rarely been reported in these patients. LPD associated with primary immunodeficiencies is frequently EBV‐driven, and marked T‐cell dysfunction is associated with poor outcomes [12]. In contrast, our patient had DLBCL with negative EBV PCR in both tumor tissue and serum.

The pathological findings were also unusual. The lesion consisted of large atypical B cells with strong CD20, diffuse BCL2, and prominent CD30 expression, but the cells were polytypic by light‐chain analysis and lacked demonstrable IgH clonality. Similar histopathological features have recently been reported in an IL2RG‐deficient patient with lymphoma [9], suggesting that B‐cell proliferations arising in profound T‐cell deficiency may have distinctive biological characteristics.

To date, only a small number of lymphoma cases associated with IL2RG deficiency have been reported [2, 4, 10, 11, 12]. Several patients demonstrated regression of lymphoma following HSCT. Trahair et al. reported a 3‐month‐old infant with a hepatic lesion who received rituximab followed by haploidentical HSCT, with subsequent regression of the lesion [10]. Mustillo et al. described a 7‐month‐old infant with a retro‐orbital mass that disappeared after complete donor T‐cell chimerism was achieved [2]. Slatter et al. reported two patients whose lesions regressed after HSCT, although one subsequently died from pulmonary hemorrhage [4]. Wada et al. described an adult with EBV‐positive LPD who responded to brentuximab but died from septic shock [11]. Rochate et al. reported a 4‐month‐old infant with EBV‐negative DLBCL who received rituximab and HSCT and remained free of lymphoma 2 years later [12] (Table 2).

TABLE 2.

Characteristics of the published cases with lymphoproliferative disorders (LPD) developed in with interleukin‐2 gamma receptor (IL2RG) mutations.

Patient/reference	Age/clinical features (including EBV status)	Pathology/immunohistochemistry	Treatment/HSCT	Outcome/follow‐up
Trahair et al. [10]	3‐month‐old; respiratory failure, hepatosplenomegaly, hepatic mass EBV PCR negative IL2RG mutation	LPD; CD20+, CD79a+. Viral PCRs negative	Rituximab (four doses) Myeloablative conditioning 5/6 MUD cord blood HSCT	Complications resolved; hepatic lesions regressed
Mustillo et al. [2]	7‐month‐old; periorbital mass, moniliasis EBV PCR negative IL2RG mutation	LPD; CD20+, EBER−	Cyclophosphamide (one dose), L‐asparaginase, vincristine (three doses), and rituximab (nine doses) 7/8 MUD, HSCT	Achieved 100% chimerism; died on Day +225 due to catheter complication infectious
Slatter et al. [4]	Pneumocystis pneumonia (PCP), soft tissue lesion EBV negative IL2RG mutation	LPD; CD20+/CD79a+, CD30+, CD15+	10/10 MRD, HSCT	Died due to pulmonary hemorrhage
Slatter et al. [4]	Jaundice, hepatosplenomegaly, rib lesion EBV PCR negative IL2RG mutation	LPD; CD30+/CD79a+, weak CD20	10/10 MRD, HSCT	Complete resolution following HSCT
Wada et al. [11]	21 years; lymphadenopathy, hemophagocytic lymphohistiocytosis (HLH) EBV PCR positive IL2RG mutation	Hodgkin‐like LPD; CD30+, IMP3+, EBER+	Brentuximab vedotin	Initial response observed; subsequently died due to sepsis
Rochate et al. [12]	4‐month‐old; periorbital mass, Pneumocystis jirovecii pneumonia, vomiting and diarrhea post‐rotavirus vaccination EBV PCR negative IL2RG mutation	DLBCL LPD; CD20+, CD30+, EBER−	Rituximab (prior to 1‐week HSCT) 10/10 MUD, HSCT	Over 2 years after HSCT and upon discontinuation of immunosuppression, the infant shows an efficient immune reconstitution, no signs of GvHD nor evidence of lymphoma recurrence
Present case	2 months; diarrhea, lymphopenia, family history EBV PCR negative IL2RG mutation	DLBCL CD20 strong+, Ki‐67 approximately 50%, EBER−	Two cycles of low dose cyclophosphamide (25 mg/kg/d) together vincristine (0.05 mg/kg/d) (prior to 1‐month HSCT) Haploidentical HSCT from father	Complete radiologic remission at 24 months posttreatment

Our patient is notable for EBV‐negative DLBCL that was refractory to rituximab and reduced‐dose chemotherapy, with severe infectious complications that prevented further cytotoxic treatment. Following unconditioned haploidentical HSCT, donor T‐cell chimerism progressively increased and the lymphoma completely regressed. Importantly, the disappearance of the lymphoma occurred in temporal association with donor T‐cell engraftment and immune reconstitution. Although a causal relationship cannot be established, these findings raise the possibility that restoration of cellular immunity contributed substantially to lymphoma control.

Lymphedema developed after HSCT, a rare complication that has previously been proposed to be associated with severe innate lymphoid cell deficiency in patients undergoing HSCT without conditioning [10] (Figure 5).

FIGURE 5.

Lymphedema in patient.

4. Conclusion

EBV‐negative lymphoma in IL2RG‐deficient SCID is exceptionally rare, and its optimal management remains undefined. This case suggests that restoration of donor T‐cell immunity may contribute to lymphoma control when conventional chemotherapy is ineffective or poorly tolerated. Successful HSCT may therefore provide both definitive immune reconstitution and an important therapeutic opportunity for lymphoma in this population.

Author Contributions

Burcu Sarıgül Cimi contributed to the study conception and design, data collection, literature review, manuscript drafting, and revision. All authors participated in the clinical management of the patient, critically revised the manuscript for important intellectual content, approved the final version of the manuscript, and agreed to be accountable for all aspects of the work.

Funding

The authors have nothing to report.

Ethics Statement

The study was conducted in accordance with the principles of the Declaration of Helsinki and institutional ethical standards.

Consent

Written informed consent for publication of this case report and the accompanying images was obtained from the patient's legal guardians. A copy of the written consent is available for review by the Editor upon request.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request. Data are not publicly available because they contain information that could compromise patient privacy.