Hodgkin lymphoma in two children with chronic granulomatous disease

To the editor:

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency (PID) characterized by a lack of reactive oxygen species (ROS) due to a defect of the NADPH oxidase in phagocytes and other cells¹, resulting in severe recurrent pyogenic and fungal infections early in life^E1. A number of PIDs are known to predispose to certain cancers²,^E2. CGD patients have been reported to have a high risk of developing solid tumors^3,4. Two cases of hematologic malignancies — one of acute lymphoblastic leukemia (ALL) in a boy with X-linked CGD⁵ and the other of splenic Hodgkin lymphoma in a 20-year old man⁶ — have also recently been reported. We describe here two cases of lymphoma in CGD patients: a man with X-linked CGD and a girl with autosomal recessive (AR) CGD.

The first patient was born in 1987 to non consanguineous parents living in France. He had an early history of repeated upper respiratory tract infections, chronic eczema, cheilitis, gingivitis, cervical lymphadenitis and recurrent otitis media by the age of three years. Staphylococcus aureus was isolated from a lymph node. He developed bronchiectasis by the age of seven years, chronic restrictive lung disease at 13 and diffuse inflammatory colitis at the age of 19. This patient was diagnosed with CGD at the age of seven, on the basis of a nitroblue tetrazolium (NBT) reduction assay (0%) and an absence of gp91^phox expression on immunoblots. RT-PCR and gene sequencing revealed a hemizygous nonsense point mutation in exon 7 of CYBB, affecting the NTERM domain (c.676[C>T], p.R226X). Prophylactic treatment with trimethoprim/sulfamethoxazole (TMP/SMZ) and itraconazole was started. The patient was hospitalized at the age of 14, after two weeks of general decline, weight loss, dyspnea and dry cough. Chest X rays and CT showed a mediastinal (left parahilar) mass. A thoracoscopy-guided transbronchial biopsy revealed abnormal cells: a lymphocyte-rich inflammatory infiltrate, consisting of large lacunar cells with large, round, eosinophilic nucleoli (Reed-Sternberg cells), together with eosinophils, histiocytes and macrophages, in a granulomatous, fibrous background. Immunophenotyping identified CD30+, LMP+, CD20−, CD3−, CD15− and ALK- cells. Stage 2Bb scleronodular type Hodgkin lymphoma was diagnosed on the basis of regional localization with constitutional B symptoms but no visceral involvement. A multiple chemotherapy regimen consisting of procarbazine, adriamycin and prednisone ([O]PPA) was initiated, for two sessions, followed by C(O)PP (cyclophosphamide, prednisone and procarbazine, without vincristine) for four more sessions. Prophylactic radiotherapy was also administered, with 30 Grays of external beam irradiation in the “mantle” field, and 20 Grays of lumbosplenic radiation, achieving complete remission. Follow-up has shown no signs of recurrence eight years after radio-chemotherapy. The patient is alive and generally well.

The second patient, a girl from Mauritius, was born in 1994 to consanguineous parents of Indian ancestry. She had no history of serious infections in early childhood. At the age of 10 years, the patient presented with a three-year history of cervical and axillary lymphadenopathy, intermittent low-grade fever and weight loss. She had been given several regimens of antituberculous medication, with poor results. On examination, the patient had diffuse, bilateral cervical and axillary lymphadenopathies, 20 to 40 mm in diameter, including an ulcerated retro-auricular lymph node. Lymph node needle biopsies showed granulomatous inflammation. No acid-fast bacilli were detected and culture was negative for bacteria, fungi and mycobacteria. Neck and chest X rays revealed multiple bilateral nodular calcifications along the trajectory of the cervical lymph node chains and mediastinum. CT-scan showed several enlarged nodes below the diaphragm and a multinodular pattern in liver and spleen. Laboratory tests reported persistent inflammation, moderate hypergammaglobulinemia, normal cellularity of the bone marrow, and serologic evidence of chronic Epstein-Barr virus (EBV) infection. Nocardia sp. grew in a culture of fluid sampled during an episode of septic arthritis of the elbow.

Over the next few months, the patient’s condition worsened, with weight loss, hepatosplenomegaly, ascites and jaundice. On admission, at the age of 10 years, the patient was found to be cachectic and severely jaundiced, with respiratory distress and rales on auscultation. Lymphadenopathy was generalized, with retroauricular spontaneous fistulization-ulceration and marked hepatosplenomegaly on palpation. The patient was febrile, anemic and thrombocytopenic. Thrombin time was moderately prolonged, and serum fibrinogen concentration was low. PCR for EBV revealed acute reactivation (15,800 viral copies/ml). Burkholderia cepacia was grown from blood cultures. All other cultures were negative. An excisional biopsy of a cervical lymph node showed caseous tuberculous lesions and calcified fibrocaseous scars, with aberrant lymph node architecture, admixed inflammatory infiltrate, thick collagen fibers and numerous Reed-Sternberg cells. Immunophenotyping of these slides confirmed the presence of mixed cellularity type Hodgkin lymphoma: CD30+, CD15−/+, CD20−, CD79a−, CD3−. A review of the previous biopsies provided no evidence of overlooked tumor cells. The patient’s condition deteriorated rapidly, with progressive respiratory distress, refractory shock, renal and hepatic failure, and diffuse multiple hemorrhages. She died on her fifth day in hospital. Cytochrome-c reduction assay in EBV-transformed B cells showed no superoxide production. Immunoblotting showed an absence of p47^phox. RT-PCR and sequencing of NCF1 revealed the mutation most commonly found in AR-CGD, a homozygous GT deletion at the beginning of exon 2. Both the patient’s younger sisters have also since been diagnosed with the same homozygous mutation, and are currently receiving prophylaxis with oral antibiotics.

Lymphomas have been associated with a number of PIDs⁷, particularly those affecting lymphocytes and immune regulation. Hodgkin lymphoma is a malignant proliferative disorder of monoclonal B-cell origin. The scleronodular type is more common in younger subjects, whereas the mixed cellularity and lymphocyte-depleted subtypes are most frequent among PID patients^E3. Isolated reports of solid cancers and hematologic malignancies in patients with CGD to date include retinoblastoma³, malignant melanoma³, rhabdomyosarcoma of the liver³, glioblastoma multiforme⁴, T-cell ALL⁵ and Hodgkin lymphoma. A case of splenic Hodgkin lymphoma in a 20-year-old CGD patient has also recently been reported⁶.

Weel et al. ³ estimated a high relative risk for cancer associated with CGD, based on epidemiologic data from the Netherlands. They hypothesized that patients with CGD display deficiencies in cytotoxicity to cancerous cells, based on early experiments showing antibody-dependent killing of tumor cells by neutrophilsE4–E6. However, the absence of malignancy reports in large CGD cohorts from the USA¹, Europe^E7 and Japan^E8, and the lack of tumor development in murine models of CGD call this assertion into question.

No direct link between NADPH oxidase and tumorigenesis has been established, although an association between polymorphisms in oxidative stress pathway components (CYBA and AKR1A1) and the development of non-Hodgkin lymphoma (NHL) has been reported⁸. Superoxide production in B cells occurs at a level only one tenth that in phagocytes^E9, and ROS in B cells are known to act principally as signaling molecules, regulating a number of cell functions, including apoptosis⁹,^E10–12. It therefore seems most likely that reactive oxygen species (ROS) act as signaling molecules in B cells, inducing apoptosis and preventing the uncontrolled proliferation of these cells. Our two cases contribute to the available evidence for a high degree of susceptibility to malignancy in CGD patients. Whether this is a true cause-effect relation, or just a spurious association of two rare diseases, remains to be determined.

Abbreviations used

AR

autosomal recessive

BCG

Bacille Calmette-Guérin

CGD

chronic granulomatous disease

EBV

Epstein-Barr virus

NADPH

nicotinamide dinucleotide phosphate

NBT

nitroblue tetrazolium

PID

primary immunodeficiencies