Eur J Pediatr DOI 10.1007/s00431-015-2508-6
ORIGINAL ARTICLE
Non-Hodgkin lymphoma in pediatric patients with common variable immunodeficiency Monica Piquer Gibert & Laia Alsina & María Teresa Giner Muñoz & Ofelia Cruz Martínez & Karen Ruiz Echevarria & Olga Dominguez & Ana María Plaza Martín & Juan I. Arostegui & Guillem de Valles & Manel Juan Otero & Maria Anunciacion Martin-Mateos
Received: 15 September 2014 / Revised: 4 February 2015 / Accepted: 13 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency associated with an increased risk of malignancy in adulthood, with lymphoma as one of the major causes of death. The aim of this study is to describe those malignancies detected in our cohort of pediatric CVID patients. We reviewed the clinical and laboratory data and the treatments and their outcomes in all pediatric CVID patients from our institution that developed a neoplasia. Four
malignancies were diagnosed in three out of 27 pediatric CVID patients. Three malignancies were non-Hodgkin lymphoma (NHL) of B cell origin (mean age at diagnosis: 8 years old), and the remaining was a low-grade astrocytoma. Among NHL, two were mucosa-associated lymphoid tissue (MALT) lymphomas and one was associated with Epstein-Barr virus infection. NHL developed before CVID diagnosis in two patients. CVID patients showed different clinical phenotypes
Communicated by David Nadal Manel Juan Otero and Maria Anunciacion Martin-Mateos share senior co-authorship. Revisions received: 05 December 2014 / 03 February 2015 M. Piquer Gibert : L. Alsina : M. T. Giner Muñoz : K. Ruiz Echevarria : O. Dominguez : A. M. Plaza Martín : M. A. Martin-Mateos Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu-Universitat de Barcelona, Passeig Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona, Spain L. Alsina e-mail: [email protected] M. T. Giner Muñoz e-mail: [email protected] K. Ruiz Echevarria e-mail: [email protected] O. Dominguez e-mail: [email protected] A. M. Plaza Martín e-mail: [email protected] M. A. Martin-Mateos e-mail: [email protected] O. Cruz Martínez Oncology Pediatric Department, Hospital Sant Joan de Déu-Universitat de Barcelona, Passeig Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona, Spain e-mail: [email protected]
J. I. Arostegui : M. Juan Otero Immunology Department–CDB, Hospital Clinic-IDIBAPS, Calle Villarroel, 170, 08036 Barcelona, Spain
J. I. Arostegui e-mail: [email protected] M. Juan Otero e-mail: [email protected]
M. Piquer Gibert (*) : L. Alsina : M. T. Giner Muñoz : O. Dominguez : A. M. Plaza Martín : J. I. Arostegui : M. Juan Otero : M. A. Martin-Mateos Functional Unit of Immunology, Hospital Sant Joan de Déu-Hospital Clinic, Barcelona, Spain e-mail: [email protected]
G. de Valles IBE-Institute of Evolutionary Biology (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Catalonia, Spain e-mail: [email protected]
Eur J Pediatr
and belonged to different groups according Euroclass and Pediatric classification criteria. Conclusions: Malignancies, especially lymphoma, may develop in pediatric CVID patients with no previous signs of lymphoid hyperplasia and even before CVID diagnosis. Consequently, strategies for cancer prevention and/or early diagnosis are required in pediatric CVID patients. What is Known: • Non-Hodgkin lymphomas are the most frequent neoplasm reported in pediatric CVID patients. • “Polyclonal lymphoproliferation” clinical phenotype is associated with increased risk of lymphoid malignancy and group smB-Trhi of the Euroclass classification with an increased risk of lymphadenopathy. What is New: • We report a higher incidence of non-Hodgkin lymphomas compared to previous publications in pediatric patients, and our patients are younger than reported. • None of our patients belongs to “polyclonal lymphoproliferation” clinical phenotype, and a common B cell subphenotyping (smB+21lo) was identified in two of lo the three patients.
Keywords Common variable immunodeficiency . Epstein-Barr virus . MALT lymphoma . Pediatric . Rituximab . Second neoplasm Abbreviations APRIL A proliferation-inducing ligand BAFF B cell activating factor CHOP Cyclophosphamide, doxorubicin, vincristine, prednisone CMV Cytomegalovirus COPADM Cyclophosphamide, vincristine, prednisolone, doxorubicine, methotrexate chemotherapy CSF Cerebrospinal fluid CT Computed tomography CVID Common variable immunodeficiency CYVE Cytarabine, etoposide FDG-PET 18-Fluoro-deoxyglucose positron emission tomography EBV Epstein-Barr virus HHV8 Human herpes virus 8 IgA Immunoglobulin A IgG Immunoglobulin G IgM Immunoglobulin M IRT Immunoglobulin replacement therapy LMB B cell non-Hodgkin lymphoma and Burkitt lymphoma/leukemia MALT Mucosa-associated lymphoid tissue NHL Non-Hodgkin lymphomas PCR Polymerase chain reaction qRT-PCR Reverse transcriptase PCR SIR Standardized incidence ratio WHO World Health Organization
Introduction Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder characterized by recurrent sinopulmonary infections, autoimmune disorders, granulomatous disease, and an increased risk of malignancy (12-18-fold over general population) [15, 18]. CVID affects both children and adults, with an estimated prevalence of 1 case per 25,000– 50,000 individuals [20]. The hallmark of CVID is hypogammaglobulinemia due to impaired B cell differentiation. CVID is a heterogeneous disease, with patients suffering mainly from infections, and others particularly prone to noninfectious complications. These differences seem to correlate with their particular B cell phenotype. Immunoglobulin replacement therapy (IRT) reduces the number and severity of bacterial infections, decreases the antibiotic use and hospitalizations, and probably enhances survival. However, IRT does not protect against the development of malignancies nor other non-infectious complications such as granulomatous disease [3, 11]. In this sense, different studies have shown that chronic lung disease and malignancies represent the major causes of death in CVID patients [4, 16, 18, 20]. CVID patients display a variety of immune and dysregulation abnormalities, but the extent to which these disorders increase the susceptibility to lymphoid malignancies is unclear. The studies reported a 12 to 259-fold increase in the risk of lymphoma in CVID patients [9, 14, 15, 18]. The Australian study with 416 CVID patients reported a SIR of 12.1 (95 % CI 6.03–21.0) of NHL [23]. The most frequently diagnosed malignancy are B cell non-Hodgkin lymphomas (NHL), usually Epstein-Barr Virus (EBV) negative, which present in the fourth to seventh decade of live [6]. They are subclassified into specific B cell phenotypes as mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, and T cell-rich B cell EBV-associated lymphoma. Several reports note that lymphoma is more common in female patients [9, 20]. Pediatric data about malignancies in CVID patients are limited. In the Urschel series, 4/32 children developed malignancy: two had Hodgkin disease and two had NHL (one of them Burkitt lymphoma) [22]. Ogershok et al. describe a patient with undifferentiated sarcoma prior to the diagnosis of CVID [17]. In the Mohammedinejad study, 7 patients had lymphoma (3 Hodgkin diseases and 1 NHL) [16]. Three malignancies (leukemia, lymphoma, and melanoma) were described in 45 pediatric patients in Yong cohort [27]. The aim of this study was to review the cases of malignancy in our cohort of pediatric CVID patients. We report three patients diagnosed with B cell lineage lymphoma, one of them associated with Epstein-Barr virus infection. One patient developed additionally a low-grade astrocytoma.
Eur J Pediatr
Methods We reviewed the clinical charts of CVID patients diagnosed at Hospital Sant Joan de Déu between 2000 and 2013. The CVID diagnosis was achieved following the criteria defined by the European Society for Immunodeficiencies and the PanAmerican Group for immunodeficiency [7]. The family histories, clinical features, laboratory findings, and treatments and their outcomes were recorded. The immune work-up to diagnose CVID included peripheral blood counts, complete T, B, and NK cells immunophenotypes, serum immunoglobulin levels, humoral response to vaccines, isohemagglutinin titters, and proliferative assays with conventional mitogens. When necessary, additional studies were performed to exclude other causes of hypogammaglobulinemia and other primary immunodeficiencies. B cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) serum levels were also quantified by conventional ELISA, develop following manufacturer’s instructions (eBioscience®); reference levels of these cytokines are the one defined in our lab. The Ethical Committee of Hospital Sant Joan de Déu approved this study. Our institution is a tertiary mother and child care center; it is a referral center for pediatric specialties. The patients reported were treated from the initial diagnosis in our institution, with the exception of the patient 3. A written informed consent was obtained from all parents.
Patients and results The pediatric CVID cohort diagnosed in our institution includes twenty-seven patients. Three of them were diagnosed with B cell lymphoma, and one out of three also developed a low-grade astrocytoma. No other malignancies were registered in this cohort during the follow-up. Detailed information on each of the three CVID patients with malignancies is presented below (See Table 1 for additional information). Patient 1 She is a 20-year-old Caucasian woman with syndactyly between 2nd and 3rd toes who presented with recurrent tonsillitis and otitis, and pneumonia at 3 and 4 years of age, respectively. Adenoidectomy was performed at 5 years. At 11 years, she presented with an inguinal tumor subsequently diagnosed as NHL (low-grade B cell marginal lymphoma, stage II). Serum anti-EBV IgG was positive. She was treated with chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days for 6 cycles) and complete remission was obtained.
At 13 years, she developed autoimmune hemolytic anemia (AIHA) that was difficult to control with steroids, requiring 2 cycles of rituximab (375 mg/m2/weekly for 4 weeks), spaced 6 months apart. At 15, 2 years after finishing rituximab, B cell lymphopenia practically recovered with persistent hypogammaglobulinemia of IgG and IgA (first detected at lymphoma diagnosis). Autoimmune lymphoproliferative disease was reasonably ruled out by normal number of double negative T cells. Then, she was diagnosed as CVID and IRT was started. At 16 years, she developed a right submandibular lymphadenopathy. Pathology studies revealed a marginal zone lymphoma (MALT type). EBV was negative by in situ hybridization and by latent membrane protein. Both neoplasms were low-grade marginal zone lymphomas, with similar histology and IHC results. Treatment with rituximab was given. A decrease of IgG, IgA, and IgM was detected at diagnosis of lymphoma (11 years old). No immunoglobulin levels were obtained before lymphoma diagnosis. Two years after finishing lymphoma treatment, and coinciding with the diagnosis of AIHA, IgM was normal (1015 mg/L (522–3350)). AIHA required treatment with monoclonal antibody rituximab, and after the second course of rituximab, IgM diminished and never reached normal age-matched values again. Three years after finishing rituximab, immunoglobulin levels: IgG 5235 mg/L (6500–15,000), IgA 540 mg/L (760–3900), and IgM 269 mg/L (400–3450). At 18 years, she was transferred to an adult center, where a recurrence of the MALT lymphoma has been recently detected. Patient 2 She is a 16-year-old girl born to first-cousin parents from North African ancestry. She was diagnosed with chronic diarrhea of unknown origin and somatic stagnation since early infancy. At 8 years, she was first visited in our institution. The physical examination revealed pallor, laterocervical lymphadenopathy, bilateral pulmonary rales, and splenomegaly. Hypogammaglobulinemia and anemia were detected. After a complete immune work-up, CVID was diagnosed and IRT started. An intestinal biopsy revealed normal villi and increased (predominantly lymphocytic) inflammatory infiltration. Pulmonary function tests showed a mixed pattern without response to bronchodilators. Thoracic computed tomography (CT) evidenced multiple pulmonary nodules and lymphadenopathies (See Fig. 1). These lesions enhanced at FDGPET. A lung biopsy confirmed a low-grade marginal zone lymphoma. There was an atypical lymphoid population of cells that presented CD20, CD79a, lambda chain restriction, and bcl-2 IHC positivity. LMP-1 and in situ hybridization for VEB RNA, as well as CD3, CD5, and CD43 were negative in
Eur J Pediatr Table 1
Clinical and laboratory characteristics of the patients related to CVID and lymphoma Patient 1
Patient 2
Patient 3
Female No
Female Yes
Male No
No Yes Yes Lymphoma (11 y)
No No No Chronic diarrhea (1 y)
No No Yes Failure to thrive (4 y)
15 y 11 m
8y
6y3m
No disease-related complications Autoimmune cytopenias Polyclonal lymphoproliferation Unexplained persistent enteropathy EUROClass group
No Yes No No smB+21loTrnorm
No No No Yes
Yes No No No
Pediatric classification IgG (mg/L) in serum at diagnosis IgA (mg/L) in serum at diagnosis IgM (mg/L) in serum at diagnosis BAFF (ng/mL) in serum APRIL (ng/mL) in serum
Group II 6565 (6700–14,300) 253 (690–2940) 98 (522–3350)
ORIGINAL ARTICLE
Non-Hodgkin lymphoma in pediatric patients with common variable immunodeficiency Monica Piquer Gibert & Laia Alsina & María Teresa Giner Muñoz & Ofelia Cruz Martínez & Karen Ruiz Echevarria & Olga Dominguez & Ana María Plaza Martín & Juan I. Arostegui & Guillem de Valles & Manel Juan Otero & Maria Anunciacion Martin-Mateos
Received: 15 September 2014 / Revised: 4 February 2015 / Accepted: 13 February 2015 # Springer-Verlag Berlin Heidelberg 2015
Abstract Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency associated with an increased risk of malignancy in adulthood, with lymphoma as one of the major causes of death. The aim of this study is to describe those malignancies detected in our cohort of pediatric CVID patients. We reviewed the clinical and laboratory data and the treatments and their outcomes in all pediatric CVID patients from our institution that developed a neoplasia. Four
malignancies were diagnosed in three out of 27 pediatric CVID patients. Three malignancies were non-Hodgkin lymphoma (NHL) of B cell origin (mean age at diagnosis: 8 years old), and the remaining was a low-grade astrocytoma. Among NHL, two were mucosa-associated lymphoid tissue (MALT) lymphomas and one was associated with Epstein-Barr virus infection. NHL developed before CVID diagnosis in two patients. CVID patients showed different clinical phenotypes
Communicated by David Nadal Manel Juan Otero and Maria Anunciacion Martin-Mateos share senior co-authorship. Revisions received: 05 December 2014 / 03 February 2015 M. Piquer Gibert : L. Alsina : M. T. Giner Muñoz : K. Ruiz Echevarria : O. Dominguez : A. M. Plaza Martín : M. A. Martin-Mateos Pediatric Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu-Universitat de Barcelona, Passeig Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona, Spain L. Alsina e-mail: [email protected] M. T. Giner Muñoz e-mail: [email protected] K. Ruiz Echevarria e-mail: [email protected] O. Dominguez e-mail: [email protected] A. M. Plaza Martín e-mail: [email protected] M. A. Martin-Mateos e-mail: [email protected] O. Cruz Martínez Oncology Pediatric Department, Hospital Sant Joan de Déu-Universitat de Barcelona, Passeig Sant Joan de Déu, 2, 08950 Esplugues de Llobregat, Barcelona, Spain e-mail: [email protected]
J. I. Arostegui : M. Juan Otero Immunology Department–CDB, Hospital Clinic-IDIBAPS, Calle Villarroel, 170, 08036 Barcelona, Spain
J. I. Arostegui e-mail: [email protected] M. Juan Otero e-mail: [email protected]
M. Piquer Gibert (*) : L. Alsina : M. T. Giner Muñoz : O. Dominguez : A. M. Plaza Martín : J. I. Arostegui : M. Juan Otero : M. A. Martin-Mateos Functional Unit of Immunology, Hospital Sant Joan de Déu-Hospital Clinic, Barcelona, Spain e-mail: [email protected]
G. de Valles IBE-Institute of Evolutionary Biology (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Catalonia, Spain e-mail: [email protected]
Eur J Pediatr
and belonged to different groups according Euroclass and Pediatric classification criteria. Conclusions: Malignancies, especially lymphoma, may develop in pediatric CVID patients with no previous signs of lymphoid hyperplasia and even before CVID diagnosis. Consequently, strategies for cancer prevention and/or early diagnosis are required in pediatric CVID patients. What is Known: • Non-Hodgkin lymphomas are the most frequent neoplasm reported in pediatric CVID patients. • “Polyclonal lymphoproliferation” clinical phenotype is associated with increased risk of lymphoid malignancy and group smB-Trhi of the Euroclass classification with an increased risk of lymphadenopathy. What is New: • We report a higher incidence of non-Hodgkin lymphomas compared to previous publications in pediatric patients, and our patients are younger than reported. • None of our patients belongs to “polyclonal lymphoproliferation” clinical phenotype, and a common B cell subphenotyping (smB+21lo) was identified in two of lo the three patients.
Keywords Common variable immunodeficiency . Epstein-Barr virus . MALT lymphoma . Pediatric . Rituximab . Second neoplasm Abbreviations APRIL A proliferation-inducing ligand BAFF B cell activating factor CHOP Cyclophosphamide, doxorubicin, vincristine, prednisone CMV Cytomegalovirus COPADM Cyclophosphamide, vincristine, prednisolone, doxorubicine, methotrexate chemotherapy CSF Cerebrospinal fluid CT Computed tomography CVID Common variable immunodeficiency CYVE Cytarabine, etoposide FDG-PET 18-Fluoro-deoxyglucose positron emission tomography EBV Epstein-Barr virus HHV8 Human herpes virus 8 IgA Immunoglobulin A IgG Immunoglobulin G IgM Immunoglobulin M IRT Immunoglobulin replacement therapy LMB B cell non-Hodgkin lymphoma and Burkitt lymphoma/leukemia MALT Mucosa-associated lymphoid tissue NHL Non-Hodgkin lymphomas PCR Polymerase chain reaction qRT-PCR Reverse transcriptase PCR SIR Standardized incidence ratio WHO World Health Organization
Introduction Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder characterized by recurrent sinopulmonary infections, autoimmune disorders, granulomatous disease, and an increased risk of malignancy (12-18-fold over general population) [15, 18]. CVID affects both children and adults, with an estimated prevalence of 1 case per 25,000– 50,000 individuals [20]. The hallmark of CVID is hypogammaglobulinemia due to impaired B cell differentiation. CVID is a heterogeneous disease, with patients suffering mainly from infections, and others particularly prone to noninfectious complications. These differences seem to correlate with their particular B cell phenotype. Immunoglobulin replacement therapy (IRT) reduces the number and severity of bacterial infections, decreases the antibiotic use and hospitalizations, and probably enhances survival. However, IRT does not protect against the development of malignancies nor other non-infectious complications such as granulomatous disease [3, 11]. In this sense, different studies have shown that chronic lung disease and malignancies represent the major causes of death in CVID patients [4, 16, 18, 20]. CVID patients display a variety of immune and dysregulation abnormalities, but the extent to which these disorders increase the susceptibility to lymphoid malignancies is unclear. The studies reported a 12 to 259-fold increase in the risk of lymphoma in CVID patients [9, 14, 15, 18]. The Australian study with 416 CVID patients reported a SIR of 12.1 (95 % CI 6.03–21.0) of NHL [23]. The most frequently diagnosed malignancy are B cell non-Hodgkin lymphomas (NHL), usually Epstein-Barr Virus (EBV) negative, which present in the fourth to seventh decade of live [6]. They are subclassified into specific B cell phenotypes as mucosa-associated lymphoid tissue (MALT) lymphoma, marginal zone lymphoma, and T cell-rich B cell EBV-associated lymphoma. Several reports note that lymphoma is more common in female patients [9, 20]. Pediatric data about malignancies in CVID patients are limited. In the Urschel series, 4/32 children developed malignancy: two had Hodgkin disease and two had NHL (one of them Burkitt lymphoma) [22]. Ogershok et al. describe a patient with undifferentiated sarcoma prior to the diagnosis of CVID [17]. In the Mohammedinejad study, 7 patients had lymphoma (3 Hodgkin diseases and 1 NHL) [16]. Three malignancies (leukemia, lymphoma, and melanoma) were described in 45 pediatric patients in Yong cohort [27]. The aim of this study was to review the cases of malignancy in our cohort of pediatric CVID patients. We report three patients diagnosed with B cell lineage lymphoma, one of them associated with Epstein-Barr virus infection. One patient developed additionally a low-grade astrocytoma.
Eur J Pediatr
Methods We reviewed the clinical charts of CVID patients diagnosed at Hospital Sant Joan de Déu between 2000 and 2013. The CVID diagnosis was achieved following the criteria defined by the European Society for Immunodeficiencies and the PanAmerican Group for immunodeficiency [7]. The family histories, clinical features, laboratory findings, and treatments and their outcomes were recorded. The immune work-up to diagnose CVID included peripheral blood counts, complete T, B, and NK cells immunophenotypes, serum immunoglobulin levels, humoral response to vaccines, isohemagglutinin titters, and proliferative assays with conventional mitogens. When necessary, additional studies were performed to exclude other causes of hypogammaglobulinemia and other primary immunodeficiencies. B cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) serum levels were also quantified by conventional ELISA, develop following manufacturer’s instructions (eBioscience®); reference levels of these cytokines are the one defined in our lab. The Ethical Committee of Hospital Sant Joan de Déu approved this study. Our institution is a tertiary mother and child care center; it is a referral center for pediatric specialties. The patients reported were treated from the initial diagnosis in our institution, with the exception of the patient 3. A written informed consent was obtained from all parents.
Patients and results The pediatric CVID cohort diagnosed in our institution includes twenty-seven patients. Three of them were diagnosed with B cell lymphoma, and one out of three also developed a low-grade astrocytoma. No other malignancies were registered in this cohort during the follow-up. Detailed information on each of the three CVID patients with malignancies is presented below (See Table 1 for additional information). Patient 1 She is a 20-year-old Caucasian woman with syndactyly between 2nd and 3rd toes who presented with recurrent tonsillitis and otitis, and pneumonia at 3 and 4 years of age, respectively. Adenoidectomy was performed at 5 years. At 11 years, she presented with an inguinal tumor subsequently diagnosed as NHL (low-grade B cell marginal lymphoma, stage II). Serum anti-EBV IgG was positive. She was treated with chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days for 6 cycles) and complete remission was obtained.
At 13 years, she developed autoimmune hemolytic anemia (AIHA) that was difficult to control with steroids, requiring 2 cycles of rituximab (375 mg/m2/weekly for 4 weeks), spaced 6 months apart. At 15, 2 years after finishing rituximab, B cell lymphopenia practically recovered with persistent hypogammaglobulinemia of IgG and IgA (first detected at lymphoma diagnosis). Autoimmune lymphoproliferative disease was reasonably ruled out by normal number of double negative T cells. Then, she was diagnosed as CVID and IRT was started. At 16 years, she developed a right submandibular lymphadenopathy. Pathology studies revealed a marginal zone lymphoma (MALT type). EBV was negative by in situ hybridization and by latent membrane protein. Both neoplasms were low-grade marginal zone lymphomas, with similar histology and IHC results. Treatment with rituximab was given. A decrease of IgG, IgA, and IgM was detected at diagnosis of lymphoma (11 years old). No immunoglobulin levels were obtained before lymphoma diagnosis. Two years after finishing lymphoma treatment, and coinciding with the diagnosis of AIHA, IgM was normal (1015 mg/L (522–3350)). AIHA required treatment with monoclonal antibody rituximab, and after the second course of rituximab, IgM diminished and never reached normal age-matched values again. Three years after finishing rituximab, immunoglobulin levels: IgG 5235 mg/L (6500–15,000), IgA 540 mg/L (760–3900), and IgM 269 mg/L (400–3450). At 18 years, she was transferred to an adult center, where a recurrence of the MALT lymphoma has been recently detected. Patient 2 She is a 16-year-old girl born to first-cousin parents from North African ancestry. She was diagnosed with chronic diarrhea of unknown origin and somatic stagnation since early infancy. At 8 years, she was first visited in our institution. The physical examination revealed pallor, laterocervical lymphadenopathy, bilateral pulmonary rales, and splenomegaly. Hypogammaglobulinemia and anemia were detected. After a complete immune work-up, CVID was diagnosed and IRT started. An intestinal biopsy revealed normal villi and increased (predominantly lymphocytic) inflammatory infiltration. Pulmonary function tests showed a mixed pattern without response to bronchodilators. Thoracic computed tomography (CT) evidenced multiple pulmonary nodules and lymphadenopathies (See Fig. 1). These lesions enhanced at FDGPET. A lung biopsy confirmed a low-grade marginal zone lymphoma. There was an atypical lymphoid population of cells that presented CD20, CD79a, lambda chain restriction, and bcl-2 IHC positivity. LMP-1 and in situ hybridization for VEB RNA, as well as CD3, CD5, and CD43 were negative in
Eur J Pediatr Table 1
Clinical and laboratory characteristics of the patients related to CVID and lymphoma Patient 1
Patient 2
Patient 3
Female No
Female Yes
Male No
No Yes Yes Lymphoma (11 y)
No No No Chronic diarrhea (1 y)
No No Yes Failure to thrive (4 y)
15 y 11 m
8y
6y3m
No disease-related complications Autoimmune cytopenias Polyclonal lymphoproliferation Unexplained persistent enteropathy EUROClass group
No Yes No No smB+21loTrnorm
No No No Yes
Yes No No No
Pediatric classification IgG (mg/L) in serum at diagnosis IgA (mg/L) in serum at diagnosis IgM (mg/L) in serum at diagnosis BAFF (ng/mL) in serum APRIL (ng/mL) in serum
Group II 6565 (6700–14,300) 253 (690–2940) 98 (522–3350)
