Early-stage Burkitt lymphoma remained in remission 7 years from diagnosis after only one cycle of chemoimmunotherapy

Abstract

Burkitt lymphoma (BL) is a rare, mature, fast-growing and highly aggressive B-cell neoplasm. It has a high-proliferation rate with distinctive genetic changes in the C-MYC oncogene. Treatment usually requires intense and frequent chemotherapy regimens with central nervous system prophylaxis as the usual regimens used for other non-Hodgkin’s lymphoma yield poor survival in BL. This report discusses a patient who was diagnosed with a stage II, high-grade BL who received one cycle of intense chemotherapy and refused further treatment. That patient remained in complete remission in his last follow-up; 7 years from diagnosis without requiring other therapies for his lymphoma.

Background

Burkitt lymphoma (BL) is a type of non-Hodgkin’s lymphoma (NHL). It is the most common NHL in children. It can be an endemic form (in children) that is commonly associated with Epstein-Barr virus infection, sporadic (usually in adults) or immune-deficiency associated. It accounts for 20%–30% of paediatric lymphomas but only for approximately 1% of adult NHL in USA.¹

BL has characteristic immunohistochemistry, which is CD10, CD20, CD19 and BCL6 positivity, BCL2 negativity and MYC rearrangement as the sole cytogenetic abnormality.²

High-intensity chemotherapy regimens with central nervous system (CNS) prophylaxis are the standard of therapy. As they have shown a superior outcome in BL patients in comparison with standard-dose chemotherapy.³ In this manuscript, we present a male patient diagnosed with a stage II BL and declined further therapy after taking his first cycle of chemotherapy. The patient continues to follow up with his haematologist, and he remained in remission 7 years from his diagnosis, with no need for any further therapy.

Case presentation

A 63-year-old African American man presented with a painless mass in the right submandibular region. He was completely asymptomatic. He has a family history of prostate and breast cancers. Physical examination showed 1–1.5 cm firm lymphadenopathy in the right submandibular and cervical regions in addition to a palpable 2.5–3 cm right supraclavicular lymph node (LN) approximately 3 cm above the clavicle. All palpable LNs were nontender and mobile. No other LNs were appreciated, and the patient had no hepatosplenomegaly. The patient is HIV negative.

Investigations

Cervical LN biopsy showed atypical large lymphoid cells with a background of prominent apoptosis, increased mitotic activity and focal areas of starry sky appearance. Immunohistochemical staining was positive for CD10, CD20, CD45 and PAX5. Ki-67 showed 100% positivity. It was negative for CD5, CD15, CD30, Fascin, EMA, ALK-1 and BCL-2. Fluorescent in situ hybridisation panel was positive for C-MYC translocation of chromosomes (8,14), suggesting BL diagnosis (figure 1).

Figure 1.

(A) Low power field shows sheets of intermediate to large-sized lymphocytes with the starry-sky background. (B) High power field shows that the lymphocytes have round to oval nuclei, coarse chromatin and prominent nucleolus. Frequent mitotic figures are present. (C) CD3/20 double stain using DAB chromogen for CD3 and red chromogen for CD20 highlights a predominance of CD20 positive cells. (D) Ki-67 highlights nearly 100% of abnormal lymphocytes.

Positron emission tomography-CT (PET-CT) scan showed active adenopathy in the right cervical, submandibular and supraclavicular LN regions (standardised uptake value (SUV) of 5.2, 7.9 and 7.4 for submandibular LNs and 14.9, 11.0 and 5.4 for supraclavicular LNs) (figure 2), consistent with stage II disease. haemoglobin was 138 g/L (130–170) and lactate dehydrogenase (LDH) was 204 unit/L (100–240). The recommendation was to start chemotherapy for BL with the HyperCVAD (hyper-fractionated cyclophosphamide, Adriamycin (doxorubicin), vincristine and dexamethasone alternating with methotrexate plus cytarabine) chemotherapy regimen. The patient decided not to pursue any therapy because he was asymptomatic, and he was concerned about the treatment’s side effects. We discussed the benefits and risks of the treatment and the potential risks of not receiving the treatment, but the patient continued to refuse it. Direct contact information was left with the patient and his family at that time in case the patient needed any help.

Figure 2.

(A) Active lymphadenopathy in the right cervical, submandibular, and right supraclavicular regions. (B) Increased SUV uptake. PET, positron emission tomography; SUV, standardised uptake value.

Two months later, the patient noticed an increase in the mass size with the discovery of additional nodes in his neck forming a conglomerate, so he decided to follow up. He continued to deny any B symptoms except for having a weight loss of approximately five pounds. Physical examination revealed the right neck mass with multiple right submental, cervical and supraclavicular lymphadenopathy of 2–3 cm. No other lymphadenopathy or hepatosplenomegaly was found.

Repeat PET-CT showed increasing abnormality in the right cervical and supraclavicular LN regions (SUV up to 9.7 and 16.3, respectively) with two new abnormal LNs in the right cervical chain with SUV of 18.3 and 21.8 (figure 3). Haemoglobin was 119 g/L and LDH was 260 unit/L. The patient confirmed that he did not have any follow-up during that period.

Figure 3.

(A) Repeat PET-CT showed increasing abnormality in the right cervical and supraclavicular in regions with noted at least two new abnormal LNS in the right cervical chain. (B) Increased SUV uptake. PET, positron emission tomography; SUV, standardised Uptake Value.

Differential diagnosis

The diagnosis was between BL and diffuse large B cell lymphoma not-otherwise specified. Given the typical immunohistochemistry for BL, the C-MYC translocation with no other cytogenetic abnormalities, and the starry sky appearance on the biopsy’s background, BL was the likely diagnosis.

Treatment

The patient agreed to pursue therapy after the progression of his disease, he was admitted to our institution. He received part A of the hyperCVAD chemotherapy regimen which included cyclophosphamide 300 mg/m², vincristine 2 mg, doxorubicin 50 mg/m² × 1, dexamethasone 40 mg. (Body Surface Area 1.88 m²), and one dose of intrathecal prophylactic methotrexate, in addition to rituximab before chemotherapy. LDH at the time of therapy was 274 unit/L. Albumin was 3.4 g/dL. White cell count was 6.8 x 10⁹/L (4.5–11x10⁹/L), haemoglobin was 114 g/L, platelets were 263 x 10⁹/L (150 –450 x 10⁹/L), uric acid 2.5 mg/dL (3.4–7.0), electrolytes panel was within normal limits. Repeated HIV testing was negative. Two-dimensional echocardiogram showed normal ejection fraction. The patient had prophylaxis with acyclovir, fluconazole, norfloxacin and allopurinol. Cerebrospinal fluid analysis was within normal limits. Allopurinol and acyclovir were continued on discharge and the patient was informed that he would need a dose of vincristine on day 11 to complete the cycle. The patient followed up for pegfilgrastim the next day. Afterward, he decided to decline therapy due to concerns about the treatment’s side effects.

Outcome and follow-up

The patient lost follow-up for a year, then presented again for follow-up. Repeat PET scan showed near-complete resolution of the lymphadenopathy of the right side of the neck and the right supraclavicular region, an 8×8 mm LN in the right neck was noted with a maximum SUV of 2.7 which was determined to be unrelated to disease (figure 4). The patient confirmed that he did not receive any further treatment in any other institution.

Figure 4.

Repeat PET-CT showed near-complete resolution of the lymphadenopathy of the right side of the neck and the right supraclavicular region. (B) an 8*8 mm ln in the right neck was noted with a maximum SUV of 2.7. PET, positron emission tomography; SUV, standardised uptake value.

Recently, the patient came back to our institution for reevaluation, he continued to be asymptomatic. Physical examination revealed a scar under the right chin with no lymphadenopathy in LN regions. He was reassured that since it had been more than 5 years since his therapy, it is unlikely for his lymphoma to recur given the aggressive nature of BL as those types of lymphomas typically recur within the first 2 years. The patient did not need any scans, he will continue to follow-up once a year with a physical examination and blood work only. On his most recent follow-up 7 years from his diagnosis, he continued to be asymptomatic, with unremarkable physical examination and laboratory findings. His lymphoma continues to be in remission.

Discussion

BL is an aggressive, fast-growing subtype of B cell NHL, it usually has a high-proliferation rate. It can involve extranodal sites such as bone marrow, gastrointestinal tract, CNS and reproductive organs. BL subtypes include endemic, sporadic and immunodeficiency associated. If left untreated, BL has high mortality and can be rapidly fatal. Early diagnosis and initiation of appropriate therapy with consideration of the possibility of tumour lysis syndrome are crucial for the best results.⁴

In a retrospective analysis by the Nordic lymphoma group from 258 patients with HIV negative BL. Two-year overall survival (OS) was only 39% for R-CHOP compared with 83% for patients treated with Hyper-CVAD and 69% for patients treated with CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, methotrexate, ifosfamide, etoposide and cytarabine) regimens.³

Rituximab-HyperCVAD is one of the effective regimens used to treat BL with a complete remission rate of 86% and a 5-year OS of 74%. Recommended duration is eight alternating courses every 21 days.^{5 6}

Spontaneous remission of NHL is a very rare encounter. It has been reported separately as one case per 80 000–100 000 in all cancers.⁷ Spontaneous remission in aggressive, high-grade NHL is rare while it is occasionally seen in low-grade lymphomas.⁸ In a case series of NHL, authors reported only two cases of spontaneous remission in 69 patients with diffuse lymphoma (2.9%) in comparison with 18 cases out of 140 in follicular lymphoma (12.9%).⁹

The literature review also revealed a case of a 16-year-old male patient who had left neck BL. Without any treatment, he went into complete remission after surgical excision of the pathological LN. The patient was asymptomatic with normal laboratory findings and bone marrow biopsy. He was followed up regularly with history, physical examination, labs and CT scans. PET-CT scan was done after a year and showed no signs of disease recurrence.¹⁰

Another case was reported for a 59-year-old male patient who was diagnosed with high-grade B-cell lymphoma not otherwise specified of para-aortic LN who underwent a LN biopsy after which the size decreased from prior CT scans and his LDH level went down to normal levels. The patient declined chemotherapy. A follow-up CT scan obtained 6 months later showed further LN size decrease and complete absence of the formerly diagnosed hypermetabolic periaortic mass on PET-CT scan.¹¹

It is interesting to observe that our patient disease progressed when he initially decided not to pursue therapy but after receiving one cycle of intense chemotherapy, his disease responded rapidly and he remained in remission despite not completing the recommended course of therapy. This could draw attention that probably a lower number of cycles can be curative in selected patients like our patient who was young, asymptomatic, and had early stage (stage II) with normal-minimally elevated LDH. This will need further randomised studies to compare the efficacy of using fewer numbers of chemotherapy cycles in selected patients to avoid unnecessary chemotherapy side effects.

Patient’s perspective.

‘I do not want to go through therapy because I feel alright, I believe things will go away. I do not want to have side effects of the medicines.’ After reassurance that the lymphoma was in remission, he was satisfied and encouraged for yearly follow-up. He stated: ‘I will continue to see you to make sure I am fine.’

Learning points.

• To present an interesting case of a high-grade Burkitt lymphoma (BL), which went into complete remission after receiving only one cycle of chemoimmunotherapy due to the patient’s non-compliance.

• We strongly emphasise the effectiveness of the hyper-fractionated cyclophosphamide, Adriamycin (doxorubicin), vincristine and dexamethasone regimen for BL treatment.

• Although in extreme rare encounters, a spontaneous resolution before or after a very short course of treatment can occur in early-stage, high-grade cases of non-Hodgkin’s lymphoma. These encounters are still considered case reports.

• In selected patients (early stage, young and asymptomatic). Less number of chemotherapy cycles could be as effective as six cycles of therapy. This will require further future studies.