Hodgkin lymphoma in an individual with TREX1-mediated Aicardi Goutières syndrome

To the Editor:

We are reporting the first case of an individual with three-prime repair exonuclease 1 (TREX1) compound heterozygous mutations associated with Aicardi Goutières syndrome features (AGS)¹ who developed classic Hodgkin lymphoma (CHL).

AGS is a rare autoimmune interferonopathy characterized by encephalopathy, characteristic neuroradiological findings and multiorgan autoinflammation. It is caused by mutations in multiple genes involved in the sensing of intracellular nucleic acids or interferon signaling.

TREX1 was the first gene associated with AGS,¹ and is linked to other autoimmune disorders.^2,3 It is documented that patients with a history of autoimmune conditions present an increased risk of developing lymphoma.⁴

The affected individual was a 17-year-old female with spastic quadriplegia, severe psychomotor delay, seizures, and chilblains. AGS was confirmed by compound heterozygous mutations in TREX1 (c.341G>A, p.Arg114His; c.667G>A, p.Ala223Thr). She was never placed on any immune-modulating therapy. Her history of AGS was further complicated by chronic gastroesophageal reflux (GER) and obstructive sleep apnea. In the months preceding her death, she experienced feeding failure, intermittent low-grade fever, episodes of diaphoresis (attributed to dysautonomia), and recurrent respiratory infections. Due to progressive worsening of overall health, limitations of care were established and she passed away.

Targeted autopsy was performed on multiple organs, including heart, lungs, and liver. The procedure showed the presence of a firm multinodular mass at the heart base (measuring 6.5 × 5.5 cm in aggregate), bilateral lungs with enlarged coalescing hilar and peripheral lymph nodes, pleural nodules, and a large firm pericardial plaque. Histologically, nodal architecture of the involved tissues was replaced by nodules separated by thick fibrous bands, surrounded by a thickened capsule. The nodules were composed of a mixed inflammatory infiltrate dominated by eosinophils and Reed–Sternberg (RS) cells. Immunohistochemical stains of select slides showed that RS cells were CD30 and multiple myeloma 1 (MUM1) positive, with a classic pattern of weak paired box 5 (PAX5) staining in comparison to surrounding lymphocytes. In situ hybridization for EBV-encoded RNA (EBER) was negative. Overall, these findings are compatible with the diagnosis of classic HL.⁵

In addition to the massive expansion of pulmonary lymph nodes, lungs showed diffuse bronchopneumonia with mixed bacterial flora foci. Sections of the liver showed diffuse steatosis and centrilobular necrosis (image details are included in Figure 1A-D,F). Post-humous review of body imaging obtained in the year before death did not demonstrate clear hilar adenopathy on chest X-ray. However, 6 months prior to her death, a chest and abdominal computerized tomography (CT) was performed to assess ongoing feeding intolerance. In hindsight, hilar adenopathy can be suspected (Figure 1E).

FIGURE 1.

Hodgkin lymphoma and systemic findings in Aicardi Goutières syndrome. (A) Gross pathology of the cardiac base showing the cut surface of the multinodular cardiac-based mass. (B) Cross-section of gross pathology of the left lung with multiple white hilar and parenchymal nodules compressing the broncho-vascular bundles. (C) Low-power histologic image of cardiac base mass showing effaced lymph node architecture with dense fibrous bands separating nodules (hematoxylin and eosin [H&E] stain, 10×). (D) Higher power histologic image of nodules showing mixed inflammatory infiltrate dominated by eosinophils and large, binucleated with two or more nucleoli cells consistent with Reed–Sternberg (RS) cells (H&E stain, 200×). Inset image: Immunohistochemical stain for CD30 highlights the RS cells staining the membrane and Golgi apparatus (CD30, 400×). (E) Chest computerized tomography (CT): Axial enhanced CT image through the chest demonstrating bilateral hilar adenopathy (arrows). (F) Histologic sections of the liver show marked diffuse large and small droplet steatosis and centrilobular necrosis (H&E stain, 40×)

Hodgkin lymphoma (HL) comprises 6% of childhood cancers. In the United States, incidence of HL is age-related and is highest among adolescents⁶ and those with a family history.⁷ Recent data suggest underlying genetic predisposition, including those genes involved in immune surveillance.^8,9 It is therefore not surprising that children with immunodeficiencies or autoimmune disease may show increased risk of developing hematologic malignancies, and specific genetic variants may impact cancer risk, even within an individual disorder.¹⁰

AGS is an early-onset rare heritable inflammatory disease with multiorgan involvement.¹¹ An association between AGS and HL has not been described in literature to date. A recent report demonstrated that a single nucleotide polymorphism (SNP) in TREX1 may correlate with lymphoma predisposition in adults with another inflammatory disorder, Sjogren’s syndrome.¹² Moreover, TREX1 may serve as a checkpoint preventing the innate immune system from sensing cells with deoxyribonucleic acid (DNA) damage, decreasing tumor immune surveillance.¹³

In this individual, it will be difficult to know if any of her late symptoms were associated with HL. The respiratory symptoms observed in the months prior to death are likely related to the patient’s recurrent aspiration and chronic lung disease. Her progressive feeding intolerance was thought to be related to autonomic dysfunction in the context of AGS.¹¹ Recurrent sterile pyrexia can be seen throughout the disease course in AGS.¹¹ Nevertheless, symptoms such as fevers, night sweats, unexplained weight loss are frequent in individuals with HL.⁵ It is possible that AGS-related multisystem illness can mask recognition of sub-acute malignancies such as HL.

The understanding that patients with AGS, in particular those on immune suppression, may have an increased risk of lymphoma and other hematologic malignancies, complicating follow-up of this already complex disorder. Unlike carcinomas, early detection of lymphoma does not improve outcomes in children. The only effective means to screen for lymphoma at this time include full-body MRI. However, full-body MRIs are costly, and in many cases involve sedation. Therefore, routine screening for lymphoma is not standard practice in cancer predisposition syndromes. However, a low threshold to evaluate for lymphoma in AGS may be warranted if new, more severe, or atypical constitutional symptoms persist despite medical intervention. Full-body MRIs would be the best radiologic approach for diagnosis.

Thus, given the role of TREX1 in cancer biology and the relative increased risk of lymphoma in individuals affected by an autoimmune disorder, HL may be secondary to this affected individual’s underlying diagnosis of AGS. We report this association in the hope that future affected individuals will benefit from recognition of the potential for lymphoma in AGS.

DATA AVAILABILITY STATEMENT

Information on data included in this paper can be requested by emailing the corresponding author and Adeline Vanderver (vandervera@chop.edu).