Case Review: Primary T-cell CNS Lymphoma in a Pediatric Immunocompetent Patient

Primary central nervous system lymphoma (PCNSL) is a very rare form of non-Hodgkin lymphoma. In most cases, PCNSL is a B cell lymphoma, making a PCNSL with T cell in origin rare. The latter often occurs in adult immunocompromised patients [1]. There is also no consensus regarding the treatment of CNS T cell lymphoma due to the paucity of confirmed cases. In general, treatment is mainly based on a regimen that includes methotrexate [2]. In this article, we present the challenging case of a 4-year-old boy who was diagnosed with refractory T-cell CNS lymphoma after initial brain biopsy was benign and who presented 2 years after end of treatment with relapsed disease, leading to his mortality.


Introduction
Primary central nervous system lymphoma (PCNSL) is a very rare form of non-Hodgkin lymphoma, occurring in less than 1% of cases. It is limited to the CNS [3,4]. In 90% of cases, PCNSL occur as diffuse large B cell lymphoma. It is rarely a T cell lymphoma [5]. PCNSL occur more often in people with immune dysfunction, which is the only known predisposing factor. If no immune dysfunction is present, PCNSL is extremely rare, making the diagnosis more challenging due to atypical presentation. It is most often seen in elderly patients. Hence, the rarest form of the diseases will be T cell PCNSL occurring in an immunocompetent pediatric patient [3]. In this article we will present a pediatric immunocompetent patient with T cell PCNSL, who was initially misdiagnosed and later presented with relapse. We will also summarize pediatric cases published in the literature with similar diagnosis, including presentation, site of disease and diagnostic tool of each case.

Case Presentation
We present the case of a 4-year-old boy who was diagnosed with refractory T-cell CNS lymphoma after initial brain biopsy was benign and who presented 2 years after end of treatment with relapsed disease, leading to his mortality. Patient initially presented to our institution at the age of 4 years old with 2 months history of progressively worsening headache and ataxia associated with severe neck pain and recurrent episodes of vomiting. Imaging done showed right cerebellar hemisphere and frontal lobe lesions, and the patient was scheduled for suboccipital craniotomy for debulking of the brain lesion. Pathology results showed no evidence of neoplasm and infectious cause was ruled out with negative tissue biopsy, negative CSF culture and meningitis panel and negative brucella and toxoplasma studies. Patient was suspected to have an inflammatory demyelinating process and was discharged home on tapering steroid schedule. However, few days later, patient presented with nystagmus, ataxia and decreased level of consciousness after steroids were tapered so he was given pulse steroids for 5 days. Good response was noted with clinical improvement, so the patient was discharged home on 6 weeks gradual tapering steroids schedule. After 1 week, patient presented again for weakness and worsening ataxia and brain MRI was repeated showing progression of brainstem lesion which was intensely avid on PET-CT. Given the patient's recurrent symptoms, positive findings on repeat brain MRI and absence of diagnosis on initial biopsy, decision was made to repeat brain biopsy.
Atypical T-cell infiltrates were noted on second biopsy with T-cell receptor gene rearrangement showing the diagnosis of T-cell CNS lymphoma. After diagnosis on 12/09/2019, patient was started on chemotherapy as per the Burkitt lymphoma protocol COPAD M8 and completed maintenance chemotherapy on 23/1/20 as per the ANHL1131 group C3 protocol. He was admitted to the hospital for episodes of febrile neutropenia requiring intravenous antibiotics during the above-mentioned course. Repeat brain MRI after end of chemotherapy showed no change in the overall size, enhancement and extent of brainstem lesion and decision was made to proceed with radiation therapy given the refractory tumor. He received whole brain radiotherapy 24 Gy followed by focal boost of the primary tumor in the brainstem to 36 Gy. Repeat imaging 2 months later showed stable brainstem lesion with decreased enhancement on brain MRI along with decrease in uptake and size of the lesion on PET CT. Patient continued to follow-up with oncology team in outpatient clinics for post-treatment surveillance for disease recurrence.
After end of treatment, patient had residual left-sided weakness and spasticity but was otherwise normal on physical exam. As part of his assessment, MRI done on 08/12/21 showed stable examination of the brain. On 25/01/21, patient presented to the outpatient clinics for regular follow-up and parents complained of one episode of headache associated with diplopia, dizziness and low-grade fever 3 days prior to presentation. Symptoms were attributed to possible viral infection given that his father tested positive for COVID-19 infection. However, symptoms persisted, and patient presented again to the clinics complaining of worsening nystagmus, ataxic gait, lethargy and decreased activity. Urgent brain CT was done and was negative for new lesions or bleed. MRI was scheduled few days later and showed new enhancing lesions adjacent to the surgical bed with multiple enhancing lesions in the left cerebellar hemisphere, left pons and cerebellar peduncles and along the cerebellar leptomeninges, associated with disease recurrence. PET CT confirmed disease recurrence with new FDG uptake in midbrain, cerebral peduncles and faint uptake in the pons. Given that the patient was hemodynamically stable with normal physical exam except for the chronic left-sided weakness, patient was discharged home on dexamethasone 4 mg every 6 hours and was scheduled for central line insertion for chemotherapy (ifosfamide, carboplatin and etoposide) for CNS T-cell lymphoma relapse. Unfortunately, patient presented earlier to the emergency department for seizure and somnolence. He was hemodynamically stable and lab workup within normal range. Urgent CT brain was repeated and showed diffuse supratentorial hypodensity with poor grey-white matter differentiation along with effacement of the sulci suggestive of brain edema ( Figure 1). No bleed, infarct or dural venous sinus thrombosis was noted. CT brain also showed re-demonstration of the enhancement along the anterior medial aspect of the surgical cavity and right cerebellar peduncle related to the known disease recurrence ( Figure 2). Patient was started on levetiracetam in addition to management of elevated intracranial pressure with head of bed elevation, intravenous hypertonic saline and dexamethasone. Neurosurgery team consulted but edema was attributed to disease recurrence, thus no intervention was indicated at that time. Patient remained somnolent overnight and decision was made to intubate the patient in order to protect his airways. He was admitted to the pediatric intensive care unit for further management.
In the intensive care unit, parents were informed about the patient's condition and poor prognosis, and they decided to proceed with low/intermediate intensity chemotherapy to avoid severe side effects so patient was started on etoposide 100 mg/m2 for 3 days. No improvement was noted after which parents decided to proceed with high dose cytarabine followed by peg asparaginase after oncology team explained its side effects and life-threatening complications. Cytarabine 2000 mg/m2 was started and after the patient received the first dose, physical exam showed left dilated pupil not reactive to light and patient had no response to pain. Urgent brain CT showed worsening diffuse cerebral edema with complete loss of with complete loss of gray-white matter differentiation and diffuse sulci and gyral effacement and white cerebellar sign (Figure 3). Multidisciplinary meeting was held with the family and parents decided to stop chemotherapy. Patient's code was changed to do not resuscitate and he passed away few days later after cardiac arrest.

Epidemiology
T cell PCNSL is a very rare disease. It was thought to only occur in immunosuppressed patients, and thus its occurrence in immunocompetent makes it far down the list of the differential diagnosis. It occurs in less than 2% of all the malignant lymphomas, and less than 1.5% of the intracranial tumors in general. 5 When PCNSL is diagnosed, it is usually B cell in origin. Previous studies of large series looking at PCNSL done in France and Japan showed that T cell lymphomas were only 3.6% in France and 8.5% in Japan [20,21]. Another large case series done in Western countries showed that the proportion of T cell origin PCNSL was only 2% of the cases, which accounted for 8 patients out of 370 [22]. This makes its occurrence not precise. In addition, T cell PCNSL is usually a disease that occur in older patients. In a large retrospective series study that was done in 12 cancer centers in 7 different countries to describe the demographics and tumor characteristics of 45 patients, their median age was 60 years old [23].

Presenting symptoms
The presentation of isolated CNS lymphoma varies according to tumor site and patient characteristics. Generally, patients with isolated CNS lymphoma present with cranial and peripheral nerve involvement. In some cases, uveitis is the initial manifestation. Patients can also present with symptoms due to leptomeningeal involvement with neuronal lymphomatosis as the sole manifestation, such as headache, difficulty speaking, altered mental status, seizures and weakness. Additional presenting symptoms include signs of elevated intracranial pressure, 6th nerve palsy, bilateral 3rd nerve palsy, mononeuritis multiplex, unilateral hearing loss, and bilateral 7th nerve paralysis [24]. A cross-sectional retrospective study conducted in Shohadaye Tajrish Hospital in Tehran, Iran, during a 25-year period (1990 -2014) showed that symptoms are often widespread and multifocal. Due to the characteristics of the disease, symptoms mainly include cognitive impairment, disorientation, slow psychomotor activity, and personality changes. Seizures is another manifestation and can develop in 2%-33% of patients. It is important to note that the most common presenting symptoms are hemiparesis (56.2%), headache (51.7%), personality disorders and cognitive impairment (26.7%), seizure (12.5%), cranial nerve palsy (10.8%), ataxia (9.7%), aphasia (9.1%), and eye involvement (4%), respectively [25].

Diagnosis and its pitfall
The diagnosis of T cell PCNSL is challenging due to the variable locations that it can present in. It could be a single tumor or a multifocal disease. The most common site is a space occupying parenchymal mass [24]. On imaging, there is no definitive pattern for diagnosis and reactive processes cannot be ruled out. T cell PCNSL could resemble an abscess, demyelinating lesion, metastatic lesion, infection or inflammatory reaction, thus making it difficult to diagnose based on imaging solely [26]. In the large retrospective study mentioned previously where 45 patients with T cell PCNSL were described, 26 (58%) of them had cerebral hemisphere involvement and 16 (36%) patients had deeper parenchymal involvement [23]. In a study looking at 18 patients with T cell PCNSL, 5 of them had leptomeningeal enhancement, in which one patient had an extensive form. Furthermore, grading of T cell PCNSL by imaging is another challenge because infiltrations in the parenchyma might not always lead to signal abnormalities. Non-specific lab findings might be found sometimes including elevated lactate dehydrogenase level [26]. As for CSF analysis for diagnosis, an elevated protein level was shown to be elevated in 19 out of 24 patients (79%) [22]. A helpful finding for diagnosis includes lymphoma cells in CSF. However, lymphoma cells should be differentiated from reactive lymphocytes. They have larger nuclei, are more irregular and might have vacuoles. These findings could help in diagnosing CNS lymphoma, mainly when leptomeningeal enhancement in present [27]. Unfortunately, this is not always the case, and diagnosis is rarely confirmed from CSF analysis alone. Thus, obtaining a tissue biopsy from the lesions itself is most often a requirement for definitive diagnosis [22]. Furthermore, even after a confirmation of T cell PCNSL, one cannot know if the T cell lymphoma is high grade or has atypical feature, which is contrary to B cell lymphomas. In some instances, a mixed lineage could be seen, including B cell, T cell and macrophages. As for the T cell markers, CD3, CD4 and CD8 are usually found. However, in the literature, cases have been reported that are CD4 positive only, CD8 positive only, both CD 4 and CD8 positive, or both CD 4 and CD 8 negative [28].

Treatment
In the abovementioned retrospective series done in 12 cancer centers, the disease specific survival time was 25 months. These results were similar to the median survival time of B cell PCNSL. The administration of methotrexate as the primary treatment was associated with better survival [23]. In a study looking at 116 patients, a combination of chemotherapy and radiotherapy was superior to radiotherapy alone, and the patients treated with chemotherapy that included high dose methotrexate (HDMTX) had better survival than those with no methotrexate regimen. Furthermore, HDMTX with high dose cytarabine gave better results than HDMTX alone [23]. In general, treatment is divided into 3 parts: surgery, whole-brain irradiation and chemotherapy.
Each part will be discussed separately below:

Surgery
Previously, literature did not recommendation CNS lymphoma resection based on the evidence that aggressive surgery may increase the risk of postoperative deficit and provide no survival benefit compared with biopsy alone. A retrospective analysis of the German PCNSL Study Group-1 (GPSG-1) trial concluded that aggressive resection of CNS lymphoma in the setting of well-circumscribed lesions correlated with improved progression-free survival, immediate relief of mass effect and facilitated rapid tapering of glucocorticoids [22].

Whole brain radiation
Whole-brain irradiation is highly effective because it generates an immediate response in patients with CNS lymphoma. However, the utility of this type of treatment in CNS lymphoma patients is limited due to 3 factors: (1) insufficient local control of lymphoma; (2) dissemination of lymphoma cells within the CSF circulation and (3) neurological effects of radiation on brain function. The overall response rate of whole brain radiation is 90%. The median survival is 11.6 months.

Chemotherapy
No prospective trials in pediatric patients with T cell PCNSL were conducted. Therefore, there is no consensus regarding the treatment of CNS T cell lymphoma and this is due to the paucity of confirmed cases. Case reports and series have demonstrated that multi-agent chemotherapy including HDMTX and cytarabine is effective in most patients [22]. So far, HDMTX (high dose methotrexate) is the backbone of most of the induction regimens and is the most significant treatment-related prognostic variable related to survival in T cell PCNSL [28]. In the few reported cases of pediatric T cell PCNSL many treatment modalities have been used, including surgical resection, radiation, chemotherapy, and most recently allogeneic stem cell transplant. Stem cell transplant emerged as a treatment option for refractory and relapsed T cell PCNSL with survival rates ranging from 51% to 70% at 5 years [18].

Conclusion
The presenting symptoms of PCNSL are varied and depend on the area of the brain that is involved. The diagnosis is challenging and requires pathology for definitive diagnosis. There is no consensus regarding the treatment of PCNSL due to paucity of cases. Our case demonstrates that PCNSL should always be on the list of the differential diagnoses even if the initial biopsy is negative. Increasing awareness of T cell PCNSL is needed to better understand the molecular biology of the disease and develop better treatment regimens. Finally, classical therapy did not work for our patient. However, other therapies such as Nelarabine or Volume  Bortezomeb or other new targeted therapies should be considered for these patients in the future.