Hepatosplenic Alpha/Beta T-cell Lymphoma as Second Malignancy in Young Adult Patient with Previously Undiagnosed Ataxia-Telangiectasia

Abstract

Ataxia-telangiectasia (AT) is a rare autosomal recessive neurodegenerative disease characterized by ataxia, radiosensitivity, telangiectases, and increased risk for hematologic malignancies. We present a case of a female diagnosed with T-cell acute lymphocytic leukemia at 13 years and subsequently with αβ subtype of hepatosplenic T-cell lymphoma (HSTCL) at 20 years. During her diagnostic work up for HSTCL, paired tumor-germline sequencing identified a diagnosis of AT. We also describe a very refractory clinical course of her αβ HSTCL, including only a brief response to multi-agent chemotherapy and an allogenic bone marrow transplant.

Introduction

Ataxia-telangiectasia (AT) is a rare autosomal recessive neurodegenerative disease caused by pathogenic variants in the ATM gene. Clinical characteristics of AT can be highly variable, and include difficulty coordinating movements (ataxia), myoclonus, radiosensitivity, neuropathy, enlarged blood vessels in the eyes and skin (telangiectases), and immunodeficiency involving both B-lymphocytes and T-lymphocytes.^1,2 In the United States, the prevalence is estimated to be 1/40,000-1/100,000 live births.³

ATM encodes a protein that is part of a kinase family with a role in DNA repair and cell cycle checkpoint control. Studies of several different tumor types, including lymphoid malignancies, have shown loss-of-heterozygosity (LOH) at the 11q22-23 region where ATM is located, further indicating its importance as a tumor suppressor.^4,5 Patients with AT have approximately a 10%-38%^4,6,7 lifetime risk of developing cancer, particularly children and young adults, with leukemia and lymphoma accounting for 85% of malignancies.⁶ Individuals who are heterozygous for a pathogenic ATM variant do not have clinical signs and symptoms of AT or its associated hematological cancer risks but females have an increased risk of developing breast cancer in their lifetime⁸ and some studies have shown heterozygous individuals have an increased risk of pancreatic cancer.⁹

Hepatosplenic T-cell lymphoma (HSTCL) is a rare type of non-Hodgkin’s lymphoma (NHL), accounting for less than 2% of peripheral T-cell lymphomas and less than 1% of NHL cases overall.¹⁰ The αβ subtype of HSTCL is exceedingly rare, with less than 30 cases reported to date.¹¹ αβ HSTCL presents with an aggressive clinical course and poor prognosis, and is typically treated with chemotherapy and hematopoietic stem cell transplantation.^11,12 Given the rarity of both AT and HSTCL, there has been neither a reported case of αβ HSTCL associated with AT nor any studies regarding the role of AT in the pathogenesis of HSTCL.

Materials and Methods

This patient was enrolled in our PEDS-MIONCOSEQ study at the time of her second cancer diagnosis. Participants in this study undergo integrative clinical sequencing (ICS) consisting of paired tumor-germline whole exome sequencing and tumor transcriptome sequencing which was IRB approved (UM-IRBMED HUM #00056496). The patient provided informed consent and received pre-enrollment genetic counseling.¹³

Results

In October 2008, a 13-year-old female presented with leukocytosis, lymphadenopathy, fever, and fatigue, and was diagnosed with T-cell acute lymphocytic leukemia. The patient received chemotherapy according to Children’s Oncology Group AALL0434 arm B, consisting of prednisone, vincristine, daunorubicin, PEG-asparaginase, intrathecal cytarabine, high dose methotrexate and nelarabine. She initially received full dose vincristine and nelarabine, but subsequently received 50% dose starting maintenance therapy due to worsening motor neuropathy. During the course of leukemia treatment, AFP levels were tested twice due to suspicion for a possible diagnosis of AT and were within normal limits at 3.0-3.7 ng/mL. The patient completed all therapy in February 2011.

At age 20, approximately 4.5 years following completion of therapy, the patient presented with progressive thrombocytopenia and lymphopenia. Soon after, she was evaluated for hepatosplenomegaly and lymphadenopathy, and underwent lymph node and bone marrow biopsies. The finding of gain of chromosome 7q in the bone marrow was supportive of a diagnosis of HSTCL and flow cytometry led to a diagnosis of αβ HSTCL specifically. Additionally, immunohistochemical stains demonstrated markedly increased, aberrant interstitial T-cells which were positive for CD3 and CD7 and negative for CD5. T-cell rearrangement studies were not completed on the specimen. There was no morphological evidence of recurrent T-lymphoblastic leukemia. Consideration of a diagnosis of AT was again discussed based on the history of ataxia and concern for underlying immune dysregulation. AFP levels were tested again at this time and were within normal limits at 2.0 ng/mL. IgG, IgA, and IgM levels were drawn multiple times during treatment and were all within low-normal range. A PET scan revealed disease in her liver and spleen. The patient received cyclophosphamide, doxorubicin, vincristine, etopiside, and prednisone chemotherapy followed by an allogenic bone marrow transplant. No significant dose modification was used for her bone marrow transplant preparative regimen, which included cyclophosphamide and 12 Gy in 6 fractions of craniospinal irradiation followed by 12 Gy in 6 fractions (delivered BID) of total body irradiation. Bone marrow was donated by the patient’s sister and donor cell chimerism testing was completed 4 times during the first 2 months post-transplant, with the highest levels of chimerism being 31% donor cells approximately 1 month post-transplant indicating full donor chimerism was not achieved. Approximately 3 months’ post-transplant, the patient was evaluated for progressive symptoms of pain, weakness, and ataxia. A PET scan revealed widespread lesions, and a renal biopsy on day 89 was consistent with recurrent disease. Given the aggressive nature of her recurrence, comfort care was initiated and she succumbed to her disease 5 months after original diagnosis.

Of note, the patient was evaluated as an infant for ataxia and weakness at an outside institution by neurology and genetics teams. However, per the family’s report no clear diagnosis was established and no interventions were recommended. The patient saw a neurologist again at age 20 following completion of her ALL therapy for motor weakness and ataxia, again no formal diagnosis was determined and her symptoms were attributed to side effects of cancer treatments. At the time of her diagnosis of αβ HSTCL the patient was using a walker due to having falls and also reported issues with fine motor skills.

Due to the patient’s second malignancy, young age, and rare diagnosis, she was enrolled on our PEDS-MIONCOSEQ study at the time of her lymphoma diagnosis for completion of paired tumor-germline whole exome sequencing. The patient had undergone a genetic evaluation in childhood but had not had genetic testing completed prior to enrollment in the PEDS-MIONCOSEQ study. Germline analysis of the patient’s peripheral blood sample identified a homozygous pathogenic variant in ATM (p.V2424G), prompting a referral to genetic counseling.

The patient’s parents were seen in our Cancer Genetics Clinic 15 months after the patient’s death. The patient’s mother underwent germline genetic testing via breast cancer panel due to her personal history of breast cancer at age 41, while the father underwent germline analysis of the ATM gene only. The patient’s mother was heterozygous for the ATM p.V2424G pathogenic variant with no other variants identified. No variants were identified in ATM in the patient’s father. Due to the discrepancy in these results, further analysis of the patient’s original research sample was completed. Analysis showed a large region of homozygosity from 11q14.1 to 11qtel (chr11 81,000,000- 135,006,135); a region of nearly 54 megabases, which includes ATM at chr11 108,199,929, consistent with uniparental isodisomy as a cause of an autosomal recessive disease in this patient.

Discussion

Here we report a patient with an extremely rare subtype of NHL in an individual with a previously undiagnosed case of AT. AT generally presents in early childhood with ataxia, immunodeficiency, and telangiectases of the eye but presentation can vary. In classic AT, generally signs are present that aid in diagnosis, including ataxia, abnormal control of eye movements, frequent infections, and laboratory abnormalities including IgA deficiency and increased AFP). About 95% of individuals with AT have AFP levels elevated above 10 ng/mL and 60-80% of children with classic AT have immunodeficiency which can include lymphopenia, frequent sinopulmonary infections, and reduced immunoglobulins levels.⁶ Progressive cerebellar dysfunction leads to most individuals with classic AT needing use of a wheelchair by age 10.⁶ In individuals with mild or atypical AT, diagnosis can be challenging especially as symptoms may be mild and/or non-specific. Clinical notes from the patient’s childhood workups for ataxia, which reportedly included neurologic and genetic evaluations, were not available. The family reports that the patient presented with ataxia around age 2, had slurred speech in childhood, and telangiectasias of the eye were present. Evaluation of the patient’s ataxia was complicated by worsening motor skills secondary to her ALL treatment, but she required a walker due to falls and reported issues with fine motor skills in adulthood.

Genotype-phenotype correlations have been reported for some specific variants in the ATM gene. Generally, homozygous or compound heterozygous truncating pathogenic variants in ATM are causative of classic or severe AT, whereas missense pathogenic variants, such as in our patient, are more consistent with mild or atypical forms of AT as some kinase activity is retained.¹⁴ This may explain the patient’s milder phenotype and normal AFP and immunoglobulin laboratory values, and our case demonstrates the difficulty in diagnosing milder forms of AT. Individuals with AT are at increased risk for malignancies due to radiation sensitivity, with hematopoietic malignancies accounting for approximately 85% of diagnoses.⁶ T-cell origin acute lymphocytic leukemia is most common in younger children while older children tend to have more aggressive T-cell leukemias. Lymphomas that present in these children are usually B-cell types. Even in mild cases of AT, malignancy is very rarely reported as the feature leading to a diagnosis of AT in late childhood or adulthood and has been noted in the literature only once prior.¹⁵ Our report also highlights the role of germline sequencing in patients with malignancy as a method of diagnosing underlying hereditary cancer predisposition syndromes.

αβ HSTCL is extremely rare and most knowledge of HSTCL is based on the more common γδ HSTCL type. A collection of 14 case reports of αβ HSTCL indicated that this subtype may be more common in females and have a broader age distribution when compared with γδ HSTCL, which typically presents in teenage or young adult males.¹⁶ There are several reports that HSTCL may be more common in individuals with immune disorders who have received immunosuppressive drugs,¹⁷ suggesting this may predispose to the development of malignancy.

Uniparental disomy (UPD) in the germline is relatively common, presenting in 1/3,500 live births,¹⁸ but the location and whether this is isodisomy or heterodisomy is key in determining whether it will result in clinical effects. UPD is well-known as a cause of genetic disorders involving imprinted genes, such as Prader-Willi syndrome, but is very rarely implicated in autosomal recessive conditions. In instances of uniparental isodisomy (iUPD), when an individual inherits two identical chromosomes, or segments of a chromosome, from one parent, homozygosity for a pathogenic variant can cause an autosomal recessive condition. More than 40 cases of autosomal recessive conditions secondary to iUPD have been described,^18–20 but iUPD of the 11q region, where ATM is located, has not previously been implicated as a cause of an autosomal recessive condition.

Due to the patient’s germline iUPD, cytogenetic studies were not able to be completed to determine if there was LOH in 11q22-23, which would have suggested that the patient’s diagnosis of AT contributed to development of disease. Due to the rare nature of both of these diseases, it is unknown if AT is a risk factor for αβ HSTCL, however, it is known that AT predisposes to lymphoid malignancies.

In summary, we present a case of αβ HSTCL diagnosed in a 20-year-old female with AT, a rare genetic condition characterized by ataxia, radiosensitivity, telangiectases, and increased risk for malignancies. αβ HSTCL is an extremely rare subtype of NHL which typically presents with aggressive disease and a poor prognosis. This is the first report of these two, rare hematological malignancies co-occurring in a single individual and their potential association, which suggests the possibility of AT predisposing to this rare subtype of HSTCL.