Common variable immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is a condition characterized by low levels of immunoglobulin (Ig) G and either IgA or IgM in the presence of recurrent infections. This disorder is associated with an increased risk of malignancy. Mucosa-associated lymphoid tissue (MALT) lymphoma is a recently recognized form of non-Hodgkin's lymphoma that is not often present in the head. MALT lymphoma in patients with CVID is rare, and until now, it has not been reported in a cranial location outside of the parotid gland. We report the cases of 2 patients who had CVID and cranial MALT lymphoma outside of the parotid gland, and we describe their successful treatment with chemotherapy.

Introduction

The primary immunodeficiencies consist of a group of disorders that are caused by abnormalities of the immune system; the most common of these disorders involve the humoral system. One of these humoral disorders is common variable immunodeficiency (CVID), which is characterized by a decrease in the level of total immunoglobulin (Ig) G in addition to a reduction in the level of either IgA or IgM. (1-5) Patients with CVID invariably experience recurrent or chronic infections, (6) and they have a 5-to-13-fold higher risk of malignancy; 7% of these malignancies are non-Hodgkin's lymphomas. (7,8)

Mucosa-associated lymphoid tissue (MALT) lymphomas constitute a recently described subset of low-grade B-cell non-Hodgkin's lymphomas that are characterized in part by their extranodal location in the marginal zones of lymphoid tissue. (9-11) MALT lymphomas in the head are rare; in fact, their incidence is not known because they were not recognized until only relatively recently. (12,13) For this reason, optimal treatment for patients with this malignancy has yet to be determined.

In 2002, Cunningham-Rundles et al were the first to report the simultaneous occurrence of both CVID and cranial MALT lymphoma, which they found in 2 patients among a larger series. (14) Both experienced a recurrence of their malignancy 2 years after initial treatment.

In this article, we report 2 new cases of concomitant CVID and cranial MALT lymphoma, and the only 2 reported cases in which the MALT lymphomas were found outside the parotid gland. The 2 patients were treated successfully with different therapeutic modalities, and both have remained in remission since the completion of their therapy more than 2 years ago.

Case reports

Patient 1. A 60-year-old white woman had been previously diagnosed with CVID, and she had been receiving intravenous immunoglobulin (IVIG) therapy once a month for the previous 5 years. Her infections were limited to one or two sinus infections per year. However, after having an upper right molar extracted, she experienced delayed healing. Eventually, swelling at the extraction site progressed to the hard palate and crossed the midline. Biopsy analysis revealed that the patient had a large-cell Lymphoma. Immunohistochemical stains were consistent with a MALT lymphoma. Subsequent computed tomography (CT) revealed the tumor had extended into the maxillary and ethmoid sinuses (figure 1). The patient was treated with dexamethasone, doxorubicin, cyclophosphamide, and vinblastine. A reduction of the tumor mass was noted after the first dose of therapy, and the lesion resolved completely within 1 year. She has remained in remission for more than 2 years.

[FIGURE 1 OMITTED] Patient 2. A 53-year-old white woman with a diagnosis of CVID had been receiving IVIG therapy for several years. She experienced fewer infections after the initiation of IVIG therapy.

On routine physical examination, bilateral proptosis was noted. CT of the orbits demonstrated a mass effect behind the globes (figure 2). A biopsy of the mass revealed that it was a low-grade lymphoma, and the results of immunohistochemical staining were consistent with a MALT lymphoma. Magnetic resonance imaging demonstrated similar tissue in the mediastinum. The patient was treated with anti-CD20 antibody therapy, and a reduction in the mass was noted immediately. The tumor resolved completely within 4 weeks. This patient has also remained in remission for more than 2 years.

[FIGURE 2 OMITTED] Discussion

CVID is a primary immunodeficiency that affects the humoral arm of the immune system and interferes with the proper production of immunoglobulins. It is characterized by a decrease in the serum IgG level in addition to a decrease in the serum level of either IgA or IgM. The number of circulating B cells in affected patients may be reduced, but they respond to appropriate in vitro stimulation with the production and secretion of immunoglobulin. After T-cell receptor stimulation, most patients also experience a decrease in the production of interleukins, possibly because of a defect in the signal transduction system of CD4 T cells. (1) In addition to abnormal immunoglobulin levels, a diagnosis of CVID is based on the presence of recurrent infections (usually affecting the sinopulmonary tract) and the exclusion of other known causes of immunodeficiency. (1-3) Patients with CVID have a higher incidence of autoimmune, gastrointestinal, and granulomatous disease and a significantly higher risk of malignancy. (6-8)

Kinlen et al reported that patients with CVID had a 5-fold higher incidence of cancer, which was primarily a reflection of a 47-fold increase in the number of stomach cancers and a 30-fold increase in the number of lymphomas. (7) Cunningham-Rundles et al found that the risk was even higher; they reported that men and women had an 8-and 13-fold increase in malignancy in general, respectively, and that women had a 438-fold higher risk of lymphoma. (8) The reasons for these higher risks are not clear, but two causes have been postulated: (1) immune dysregulation, which alters the immune system's ability to identify and destroy malignant cells, and (2) repeated or chronic antigen stimulation, which may lead to abnormal immune system activation. (15) According to the latter hypothesis, the higher risk of lymphoma in CVID patients might be attributable to the chronic stimulation and proliferation of lymphocytes. (7,14)

MALT lymphomas are a recently recognized type of non-Hodgkin's lymphoma. They are characterized by the presence of a heterogeneous population of malignant cells--including centrocyte-like cells, lymphocytes, and plasma cells--in the marginal zones of extranodal lymphoid tissue. Immunophenotyping of these tumor cells reveals that they express surface immunoglobulins and B-cell antigens but lack CD5, CD10, and CD23. (11) MALT lymphomas can arise anywhere in the body, but initial presentation in a cranial site is extremely rare; as a result, the incidence of cranial MALT lymphomas is unknown. Therapeutic modalities have included local excision, radiation therapy, and chemotherapy, and responses have been generally favorable. (12,13)

MALT lymphomas in patients with CVID are rare. Reichenberger et al reported a case of a pulmonary MALT lymphoma. (16) One year later, Cunningham-Rundles et al reported a series of 5 patients with various MALT lymphomas, 2 of whom had cranial tumors. (14) Both of these tumors were in the parotid gland, a well-established location for cranial MALT lymphomas. (12,13) One of these patients underwent excisional and radiation therapy of the parotid tumor and experienced a number of extracranial recurrences beginning 2 years later; she was treated with repeat excision and chemotherapy. The other patient underwent excisional therapy without radiation and experienced an extracranial recurrence within 2 years; she was then treated with chemotherapy.

The location of the MALT lymphomas in our 2 patients was unusual; in fact, such a location has not been previously reported in patients with CVID. In addition, our 2 patients were initially treated with systemic therapy rather than local therapy, and both have been in remission for more than 2 years. Although immunocompetent patients with cranial MALT lymphomas have been successfully treated with local therapy, immunocompromised patients with CVID appear to experience better outcomes if they are treated initially with systemic therapy. These different outcomes may be the result of immune system dysregulation in patients with CVID, which limits the body's ability to identify, contain, and destroy malignant cells and which can lead to an early metastasis of this usually low-grade malignancy.

In summary, this article is the first report of any CVID patients with cranial MALT lymphoma that did not involve the parotid gland. Our experience suggests that patients with CVID and MALT lymphoma may experience a better outcome if they are initially treated with systemic therapy rather than local therapy.

References

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From the Department of Medicine and the Department of Pediatrics, University Hospitals of Cleveland (Dr. Tcheurekdjian), the Department of Otolaryngology, Medical College of Toledo, Ohio (Dr. Jenkins), and the Department of Pediatrics, Case Western Reserve University, Cleveland (Dr. Hostoffer).

Reprint requests: Robert Hostoffer, DO, 1611 S. Green Rd., South Euclid, OH 44121. Phone: (216) 381-3333; fax: (216) 381-3002; e-mail: r.hostoffer@direcway.com

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