Case Study. Clonal Lymphoproliferations in a Patient With Common Variable Immunodeficiency

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1 Clonal Lymphoproliferations in a Patient With Common Variable Immunodeficiency Sarah A. Williams, MD, 1 * Laura E. Moench, MD, 1 Fatima Khan, MD, 2 Gregory Vercellotti, MD, 2 Michael A. Linden, MD, PhD 1 Laboratory Medicine 47:4: ABSTRACT Common variable immunodeficiency (CVID) comprises a heterogeneous group of disorders of humoral immunity, characterized by marked deficiencies in serum immunoglobulins. Immune dysregulation causes susceptibility to recurrent bacterial infections, as well as autoimmune and lymphoproliferative disorders. Although the lymphoid cells comprising the atypical proliferations are often clonally related, their malignant potential and clinical significance differ from similar lesions in individuals with immunocompetence. Herein, we describe a Caucasian woman with CVID who over 7 years developed multiple clonal lymphoproliferative lesions, comprising a spectrum of morphologic characteristics. Many of the lesions harbored distinct clonal populations. Though a majority responded to conservative intervention, 1 lesion persisted, met the diagnostic criteria for diffuse large B-cell lymphoma, and responded well to conventional chemotherapeutic treatment. The patient subsequently developed additional lymphoproliferations, but the lesions were clonally distinct and responded to conservative therapy. The clinical course of this patient emphasizes the variable nature of lymphoproliferative lesions arising in patients with CVID and underscores an individualized approach to pathologic interpretation and diagnostic intervention. Keywords: common variable immunodeficiency (CVID), lymphoproliferative disorders, diffuse large B-cell lymphoma, Epstein-Barr virus (EBV), extranodal lymphoma, polymorphous lymphoproliferations Common variable immunodeficiency (CVID) is a primary defect of humoral immunity that is often diagnosed during the third through fifth decades of life. 1 It is characterized by significantly reduced concentrations of immunoglobulin G (IgG), immunoglobulin A (IgA), and/or immunoglobulin M (IgM), with decreased or absent specific antibody Abbreviations: CVID, common variable immunodeficiency; IgG, immunoglobulin G; IgA, immunoglobulin A; IgM, immunoglobulin M; ICOS, inducible T-cell co-stimulator; TNFRSF13B, tumor necrosis factor receptor superfamily 13B; CD, cluster of differentiation; IVIG, intravenous immunoglobulin; ITP, immune thrombocytopenic purpura; EBER-ISH, Epstein-Barr virus positive via in situ hybridization; IHC, immunohistochemistry; PCR, polymerase chain reaction; IgH, immunoglobulin heavy chain; PET, positron emission tomography; CT, computed tomography; SUV, standard uptake value; H&E, hematoxylin-eosin; CHOP, cyclophosphamide, doxorubicine hydrochloride, vincristine, prednisone; DLBCL, diffuse large B-cell lymphoma; ISH, in situ hybridization; NT, not tested; bx, biopsy; FC, flow cytometry 1 Division of Hematopathology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, USA 2 Division of Hematology, Oncology, and Transplantation, Department of Medicine, Medical School, University of Minnesota, Minneapolis, MN *To whom correspondence should be addressed. ande8350@umn.edu production. 2-4 T-cell deficiencies have also been attributed to the defective antibody response. 5 Dropulic and Cohen 6 summarized the numerous genetic abnormalities that have been identified as contributing to this heterogeneous disorder, which include mutations in B-cell related inducible T-cell costimulator (ICOS), tumor necrosis factor receptor superfamily 13B (TNFRSF13B), and abnormalities involving the members of the cluster of differentiation (CD)19 B-cell receptor complex. Recurrent sinopulmonary infections are among the most common manifestations. 1,3,7,8 The prevalence of CVID is believed to comprise 35% of patients diagnosed with primary immunodeficiency in the United States. 9 The incidence of lymphoid malignant neoplasms is increased; studies from Europe have shown a 12- to 18-fold increased risk of developing lymphoma compared with the general population. 8,10 Patients with CVID can develop polymorphic or monomorphic lymphoproliferative disorders that are often of indeterminate malignant potential and pose diagnostic and therapeutic challenges. 5,11-13 Herein, we describe the clinical course of a young woman who was diagnosed with CVID in childhood and developed multicentric involvement by B-cell lymphoproliferative lesions during the course of several years. 318 VC American Society for Clinical Pathology, All rights reserved. For permissions, please journals.permissions@oup.com

2 Case Report At the time of case submission, the patient was a 31-yearold Caucasian woman who was diagnosed with CVID as a 7-year-old child and was subsequently treated with immunoglobulin replacement (intravenous immunoglobulin [IVIG]). Shortly after starting therapy, she developed immune thrombocytopenic purpura (ITP), which responded to high-dose IVIG. The patient continued to experience recurrent herpes zoster, sinusitis, conjunctivitis, upper respiratory tract infections, and cutaneous fungal infections; however, she did not develop any lifethreatening complications. When she was 21-years-old, she developed multiple slightly erythematous, poorly marginated indurated skin lesions on her back and mid-abdomen, and an enlarged lymph node arising in the right antecubital fossa. Biopsies (Table 1) of these three separate lesions collected during a period of several months revealed similar polymorphous lymphoproliferations, with effacement of the normal tissue architecture by a vaguely nodular infiltrate of lymphoid cells. There was a predominance of small and plasmacytoid lymphocytes and some intermediate to large lymphoid cells with vesicular nuclei and small basophilic nucleoli. The right antecubital fossa lymph node and mid-abdomen skin biopsy (Table 1) were further evaluated and shown to both be Epstein-Barr virus (EBV) positive by in situ hybridization (EBER-ISH) and kappa-restricted by immunohistochemistry (IHC). The large atypical cells were highlighted with CD20, and the small lymphoid cells labeled as CD3/CD5-positive T lymphocytes. We also sent portions of the antecubital fossa lymph node for cytogenetics and molecular evaluations. Polymerase chain reaction (PCR) analysis yielded positive results for a clonal rearrangement of the immunoglobulin heavy chain (IgH) gene. The diagnosis of immune-related EBV-positive kapparestricted polymorphous B-cell lymphoproliferative lesions prompted further evaluation. A positron emission tomography (PET) computed tomography (CT) scan obtained later that month revealed hypermetabolic cutaneous lesions, hypodense splenic lesions, and enlarged lymph nodes distributed throughout the abdomen and pelvis, including a cm lobular left adnexal mass with a maximal standard uptake value (SUV) of The lymphadenopathy impinged on the left ureter, creating left-sided hydroureter and hydronephrosis. To spare the patient from a more invasive procedure, a more superficial metabolically active nodule within the anterior abdominal wall was sampled by ultrasound guided needle core biopsy; the results confirmed an EBV-positive B-cell lymphoproliferative disorder (Table 1). The hematoxylin-eosin (H&E) sections showed fragments of fibromuscular and fibroadipose tissue, with scattered and focally dense lymphoid infiltrates composed of aggregates of CD20/CD79a-positive B cells with increased cell size, within a background of small CD3-positive T cells. EBER- ISH highlighted a few positive labeling cells within B-cell predominant areas. In contrast to the kappa-restricted plasmacytoid populations appreciated within the skin biopsy and antecubital lymph node by IHC, this anterior abdominal wall nodule was composed of lambdamonoclonal B cells by flow cytometric immunophenotyping. This discrepancy suggested the possibility of more than one EBV-driven B-cell clone giving rise to lymphoproliferative lesions in this patient. PET/CT imaging obtained after 4 cycles of rituximab (375 mg/m 2 ) demonstrated significant interval decrease in disease burden with markedly diminished abdominal lymphadenopathy, near-complete regression of cutaneous lesions, and resolution of the left-sided hydroureter and hydronephrosis. Persistent areas of PET avidity were isolated to the left adnexa and near the sacrum. On account of the marked reduction in PET avid cutaneous lesions and lymphadenopathy with rituximab alone, additional cycles of rituximab were suspended, and CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisone) chemotherapy was not initiated. One month later, the left adnexal mass had decreased in size but remained hypermetabolic on PET/CT imaging. Subsequently, the patient underwent diagnostic laparoscopy with left ovarian biopsies (Table 1 and Image 1), which revealed an immunodeficiency-related, EBV-negative diffuse large B-cell lymphoma (DLBCL) with lambda light chain restriction and absence of CD5 and CD10, as demonstrated by cell-surface flow cytometric immunophenotyping. H&E-stained sections showed architectural effacement by a diffuse cellular infiltration of predominantly larger cells with irregular nuclear contours, Lab Medicine 2016;47;

3 Table 1. Biopsy Characteristics From Our Patient, a Caucasian Woman, Organized by Patient Age at Time of Collection Age (y) Site Light-Chain Restriction 21 Skin, left mid back 21 Lymph node antecubital fossa 21 Skin, mid abdomen EBV (EBER- ISH) Clone (by PCR) Morphologic Interpretation NT NT NT Granulomatous dermatitis, later reviewed and interpreted as a polymorphous lymphoproliferative disorder Kappa B/plasmacytoid þ NT Polymorphous lymphoproliferative cells (IHC) disorder Kappa B/plasmacytoid cells (IHC) þ Positive B-cell clone: different from the clones detected in the lymph node biopsy (age, 27 years) and the upper back skin bx (age, 28 y) Polymorphous lymphoproliferative disorder 21 Abdominal mass Lambda B-cells (FC) þ NT EBV-positive B-cell proliferation 22 Adnexa/ovary Lambda B-cells (FC) B-cell clone not detected EBV-negative DLBCL 27 Lymph node, axilla Kappa B-cells (FC) Suspicious for B-cell clone: Identical to the clone identified within the Polymorphous lymphoproliferative disorder upper back skin bx (age, 28 y) Different from the clone detected in the abdominal skin bx (age, 21 y) 27 Floor of mouth Plasma cells are skewed to lambda (ISH) Rare þ cells NT No convincing evidence of lymphoma 28 Skin, right upper back Kappa B/plasmacytoid cells (ISH) þ Positive B-cell clone: Identical to the clone identified within the lymph-node bx (age, 27 y) Different from the clone detected in the abdominal skin bx (age, 21 y) Polymorphous lymphoproliferative disorder EBV, Epstein-Barr virus; EBER-ISH, EBV positive via in situ hybridization; PCR, polymerase chain reaction; NT, not tested; IHC, immunohistochemistry; þ, positive; bx, biopsy; FC, flow cytometry; -, negative; ISH, in situ hybridization; DLBCL, diffuse large B-cell lymphoma. vesicular chromatin, and small basophilic nucleoli with infiltrating small round lymphocytes. The larger lymphoid cells labeled with CD20, while the smaller lymphocytes were T cells and highlighted with CD3 by IHC (Image 1). EBER-ISH was negative. The ovarian lymphoma was morphologically distinct with sheets of large atypical lymphoid cells with only a few infiltrating small lymphocytes. These results contrasted with the previously diagnosed lymphoproliferative lesions, which were predominantly composed of small lymphoid cells with a minority of large lymphoid cells. This was considered evidence of disease progression. Treatment with rituximab was resumed. CHOP chemotherapy continued to be withheld out of concern for the high risk of infection due to excessive immunosuppression of CVID combined with chemotherapy. The patient tolerated 4 additional cycles of rituximab without complications, and the multiple cutaneous lesions resolved completely. Nevertheless, 2 months after rituximab was resumed, PET/CT imaging continued to reveal hypermetabolic activity within the left adnexa. Despite multiple cycles of rituximab, PET avidity persisted within the area of biopsy-proven EBV-negative DLBCL. Consequently, CHOP chemotherapy was initiated along with rituximab, with the intent to cure. Antiviral, antibacterial, and antifungal prophylaxis was also administered during the course of chemotherapy. After 4 cycles of R-CHOP, PET/CT imaging demonstrated remission. The patient then received 2 additional cycles of R-CHOP. The patient continued to be followed clinically with serial PET/CT scans. When she was 27 years old, she developed a right axillary mass (Table 1), which showed an EBV-negative atypical lymphoid proliferation, without evidence of large-cell transformation. Flow cytometric immunophenotyping reported a small kappa-monotypic B cell population that lacked CD5 and CD10. This lesion appeared to be similar to the previous EBV-driven polymorphous lymphoproliferative lesions and spontaneously regressed over the course of the next few months without therapy. 320 Lab Medicine 2016;47;

4 A B C D CD20 E Side Scatter SSC-H P2 κ FITC FL1-H λ PE FL2-H CD45 PerCP FL3-H CD20 APC FL4-H CD20 APC FL4-H Image 1 Results from the left ovarian biopsy obtained when our patient, a Caucasian woman, was 22-years-old. All images were captured using an objective lens. A, Low-power examination demonstrates architectural effacement by a diffuse cellular infiltration (hematoxylin-eosin [H&E] staining; original magnification, 4). B, The atypical infiltrate is comprised of an admixture of small round lymphocytes and larger lymphoid cells (H&E staining; original magnification, 20). C, The atypical large lymphoid cells are characterized by irregular nuclear contours, vesicular chromatin, and small nucleoli (H&E staining; original magnification, 100; oil immersion). D, Results of testing for cluster of differentiation (CD)20 (immunohistochemistry [IHC] labeling; original magnification, 20). E, Representative flow cytometry plots. The lymphocyte gate, designated as P2, is characterized by low-side-scatter and bright CD45 expression. The P2 population is further evaluated by CD20 versus light chains, with demonstration of lambda light-chain restriction in the CD20-positive events. Lab Medicine 2016;47;

5 A B C D CD20 E F CD138 EBER G H Kappa Lambda Image 2 Results of the skin punch biopsy of the poorly marginated indurated nodule arising on the right superior lateral back, obtained when our patient, a Caucasian woman, was 28-years-old. All images were captured using an objective lens. A, Superficial punch biopsy demonstrating sparing of the epidermis with a dense lymphoid infiltrate surrounding adnexal structures within the dermis (hematoxylin-eosin [H&E] staining; original magnification, 4). B, The hypodermis is diffusely effaced by a dense lymphoid infiltration (H&E staining; original magnification, 4). C, The infiltrate consists of small to medium-sized lymphocytes with vesicular chromatin and small basophilic nucleoli, plasma cells, and rare eosinophils. Mitoses and necrosis are not identified (H&E staining; original magnification, 50; oil immersion). D, Results of testing for cluster of differentiation (CD)20 (immunohistochemistry [IHC] labeling; original magnification, 20). E, Testing for CD138 (IHC labeling; 50; oil immersion). F, Epstein-Barr virus (EBV) RNA is detected (in situ hybridization [ISH] labeling; original magnification, 50; oil immersion). G, Numerous cells label with kappa immunoglobulin light chains (ISH labeling; original magnification, 50; oil immersion). H, Rare to absent cells labeled with lambda immunoglobulin light chains (ISH labeling; original magnification, 50; oil immersion). 322 Lab Medicine 2016;47;

6 Eleven months later, the patient sought treatment at a dermatology clinic out of concern for a poorly marginated indurated nodule that had arisen on her right superior lateral back. A punch biopsy (Table 1 and Image 2) revealed an EBV-positive atypical lymphoid infiltrate, which was composed of predominantly small lymphocytes and plasmacytoid lymphocytes and was kappa-restricted by in situ hybridization (ISH) evaluation (Image 2). The B-cell gene rearrangement study by PCR demonstrated a B-cell clone. The patient was treated with rituximab and responded favorably. Retrospectively, paraffin-embedded tissue from the right axillary lymph node (collected when the patient was 27 years old) was submitted for PCR analysis. The results demonstrated a prominent peak that was identical to the clonal B-cell gene rearrangement detected within the right upper-back skin biopsy collected 11 months later. These 2 specimens demonstrated similar polymorphous lymphoid infiltrates and were both restricted for kappa light chains. However, the skin biopsy appeared to reveal an EBV-driven process with EBER-ISH positive cells, which were absent in the right axillary lymph node. In contrast, the B-cell gene rearrangement detected within the EBV-driven kapparestricted atypical lymphoid proliferation of the midabdominal skin biopsy (collected 6 years earlier when the patient was 21 years old) was distinct from the clonal rearrangements detected in the later specimens. This difference was evident despite the fact that all 3 lesions demonstrated similar morphologic characteristics and the same light chain restriction. Of note, PCR analysis failed to detect a clonal rearrangement within the DLBCL that arose within the left ovary/adnexal mass. In summary, this 31-year-old Caucasian woman with CVID has experienced multicentric involvement by B-cell lymphoproliferative lesions during the course of several years. Numerous biopsies revealed polymorphic lymphoproliferative disorders or atypical lymphoproliferative infiltrates that were clonal based on flow cytometric, IHC, ISH, or molecular techniques, yet regressed without treatment or with rituximab only. Clones varied by EBV status, light-chain restriction, and clonal peaks by PCR B- cell gene rearrangement studies. These findings suggest the presence of more than one clonal B-cell process. Also, the patient developed an immunodeficiency-related DLBCL that failed to resolve with rituximab alone and required R-CHOP chemotherapy. Characteristics of the specimens from the patient are organized chronologically in Table 1. For the past 3 years, the patient has remained in remission without rituximab therapy. Her recent clinical course has been complicated by a Nocardia infection involving the CNS and lungs. She remains on IVIG therapy. Discussion The diagnosis of CVID carries an increased mortality risk due to infectious and noninfectious complications. Although the incidence of bacterial infections has been markedly reduced by replacement immunoglobulin therapy, the threats from noninfectious complications, particularly malignant neoplasms, have remained a significant concern. 2,5,7 Patients with CVID are at an increased risk of developing lymphomas, specifically B-cell lymphomas, possibly due to the underlying immune dysregulation and sustained activation and accelerated proliferation of lymphocytes during chronic infections, increasing the risk of malignant transformation. 5,10,11,14 Nevertheless, Sander et al 13 noted that although the altered nodal architecture within lymph nodes and florid lymphoid infiltration at extra nodal sites in patients with CVID are concerning and may mimic lymphoma, the vast majority of the cases are benign. They asserted that interpretation can be aided by IHC and B-cell gene rearrangement studies. This issue is further complicated by the fact that B-cell gene rearrangement studies may be misleading in patients with CVID because these patients are known to mount small clonal B- and T-cell populations due to chronic infections and impaired antibody response. 12 A recent study 15 demonstrated that patients with CVID exhibited abnormal clonal expansions of unmutated or naïve B cells relative to healthy control individuals, irrespective of a previous diagnosis of a B-cell neoplasm. We did not implement the described method of high-throughput DNA sequencing of blood specimens looking for clonal populations (including mutational status) within sorted naïve and memory B-cell populations for our patient. However, the study results provide further support that some B-cell clones are inconsequential and that molecular clonality does not equate to malignancy in patients with CVID. A key principle of this case, as well as the cases of others with CVID, is that clonality is not synonymous with malignant neoplasia. Gompels et al 12 retrospectively Lab Medicine 2016;47;

7 reviewed biopsy specimens from patients with antibody deficiencies; 12 out of 18 specimens with reactive or normal histology had detectable IgH clonal products, or B- cell gene rearrangements, by PCR evaluation of the paraffin-embedded tissue. The research group concluded that isolated evidence of clonality should not render a diagnosis of lymphoma. Likewise, different and recurrent clonal B-cell gene rearrangements were identified in all three of our patient s polymorphous lymphoproliferative lesions which had portions summited for molecular analysis. All of these lesions either spontaneously regressed or resolved with rituximab therapy alone and were deemed nonmalignant. In contrast, a clonal B-cell gene rearrangement was not identified within the left ovarian within our patient s left ovarian DLBCL. This counterintuitive finding was also appreciate by Gompels et al, 12 who reported 3 specimens of B-cell lymphoma which demonstrated polyclonal IgH patterns by PCR analysis. Their findings illustrate the alternative point that the lack of molecular evidence of clonality should not deter the diagnosis of lymphoma when there is morphologic evidence of disease. Therefore, biopsy evaluation to assess for lymphoma in patients with CVID should be interpreted with extreme caution to avoid the morphologic and ancillary testing pitfalls present in this patient population. Neither clonality studies by IHC, ISH, flow cytometric immunophenotyping, nor EBV status by ISH were able to distinguish indolent proliferations from malignant neoplasms. The difference between DLBCL and polymorphous lymphoproliferations is a morphologic interpretation, depending on the density of large atypical cells and diffuse proliferation with lack of a follicular dendritic cell meshwork. The DLBCL, which was composed of sheets of large atypical cells, demonstrated a more aggressive clinical course which was resistant to rituximab monotherapy and required CHOP chemotherapy. On the other hand, the polymorphous lymphoproliferations, composed of predominantly small lymphocytes, resolved spontaneously or with rituximab alone. Overinterpretation, with an inappropriate emphasis placed on clonality studies, may lead to the overtreatment of these already-immunocompromised patients with cytotoxic chemotherapy regimens, which would put them at an unnecessary risk for infectious complications, therapy-related myeloid neoplasms, and/or bone marrow failure. The timing and appropriateness of therapy was addressed by da Silva et al 11 in reporting on 3 cases of patients with CVID who developed multiple lymphomatous lesions which either spontaneously resolved or responded to antibiotics alone. Chemotherapy was initiated without adverse effects from the delay in treatment. Only when clear disease progression was appreciated by imaging and symptomatology was chemotherapy initiated without adverse effects from the delay in treatment. Similarly, in our case, as a result of previous experience, active surveillance with the help of PET/CT imaging allowed for the avoidance of unnecessary overtreatment of these lymphoproliferations of indeterminate malignant potential, thereby postponing the complications of chemotherapy in an already immunocompromised patient until the point when intensified therapy was deemed necessary. Hence, CHOP chemotherapy was not initiated when the diagnosis of DLBCL was rendered, but as a reaction to the failure of the conservative approach of rituximab monotherapy. Additionally, our patient did not experience negative effects from the delay in treatment. In conclusion, pathologic evaluation of tissues in patients with CVID can be challenging because of the altered architecture within lymph nodes and marked lymphoid infiltration involving extra nodal sites. Patients with CVID have increased susceptibility toward developing lymphoma, which is a major noninfectious cause of morbidity. 2,5,7 Even so, while many of these lesions can mimic lymphoma, most represent benign reactive lymphoproliferations. 11,13 Molecular studies for detecting B-cell clonality can be misleading, with transient and reactive expansions of B cells producing clonal results on gene rearrangement studies 12 or, as in our patient, by light chain restriction. Our case illustrates these diagnostic difficulties, and our conservative diagnostic and therapeutic approaches to this patient exemplify an individualized approach to lymphoproliferations in a patient with CVID. LM References 1. Chapel H, Lucas M, Lee M, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112(2): Abbott JK, Gelfand EW. Common variable immunodeficiency: diagnosis, management, and treatment. Immunol Allergy Clin North Am. 2015;35(4): Resnick ES, Moshier EL, Godbold JH, et al. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119(7): European Society for Immunodeficiencies Registry Working Party. New Diagnostic Criteria for the ESD Registry. Registry/Diagnosis-criteria. Accessed June 11, Gangemi S, Allegra A, Musolino C. Lymphoproliferative disease and cancer among patients with common variable immunodeficiency. Leukemia Res. 2015;39(4): Lab Medicine 2016;47;

8 6. Dropulic LK, Cohen JI. Severe viral infections and primary immunodeficiencies. Clin Infect Dis. 2011;53(9): Cunningham-Rundles C. How I treat common variable immune deficiency. Blood. 2010;116(1): Quinti I, Soresina A, Spadaro G, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol. 2007;27(3): Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol. 2007;27(5): Mellemkjaer L, Hammarstrom L, Andersen V, et al. Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: a combined Danish and Swedish study. Clin Exp Immunol. 2002;130(3): da Silva SP, Resnick E, Lucas M, et al. Lymphoid proliferations of indeterminate malignant potential arising in adults with common variable immunodeficiency disorders: unusual case studies and immunohistological review in the light of possible causative events. J Clin Immunol. 2011;31(5): Gompels MM, Hodges E, Lock RJ, et al. Lymphoproliferative disease in antibody deficiency: a multi-centre study. Clin Exp Immunol. 2003;134(2): Sander CA, Medeiros LJ, Weiss LM, et al. Lymphoproliferative lesions in patients with common variable immunodeficiency syndrome. Am J Surg Pathol. 1992;16(12): Suarez F, Lortholary O, Hermine O, Lecuit M. Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood. 2006;107(8): Roskin KM, Simchoni N, Liu Y, et al. IgH sequences in common variable immune deficiency reveal altered B cell development and selection. Sci Transl Med. 2015;7(302):302ra ra Lab Medicine 2016;47;