Common Variable Immunodeficiency

Background

CVI represents the most frequent of the primary specific immunodeficiency diseases among populations of European origin. It is a defect of immunoglobulin production. The most common clinical presentation of CVI is an increased susceptibility to infection, most notably recurrent or chronic sinopulmonary infections and chronic Giardia lamblia intestinal infection. Other autoimmune and inflammatory disorders such as inflammatory bowel diseases may develop.

CVI may be associated with malignancy, in particular lymphomas, similar to other immunodeficient states.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/
Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

SYNONYMS CVI

AGE RANGE-MEDIAN Second or third decade of life

DISEASE ASSOCIATIONS CHARACTERIZATION

Peripheral T cell lymphoma in a patient with common variable immunodeficiency disease: case report and literature review.

Gottesman SR, Haas D, Ladanyi M, Amorosi EL.
Leuk Lymphoma 1999;32:589-95.

Common variable hypogammaglobulinemia complicated by an unusual T-suppressor/cytotoxic cell lymphoma.

Durham JC, Stephens DS, Rimland D, Nassar VH, Spira TJ.
Cancer 1987;59:271-6

Common-variable immunodeficiency-related lymphomas associate with mutations and rearrangements of BCL-6: pathogenetic and histogenetic implications.

Ariatti C, Vivenza D, Capello D, Migliazza A, Parvis G, Fassone L, Buonaiuto D, Savinelli F, Rossi D, Saglio G, Gaidano G.

Department of Medical Sciences, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.

Hum Pathol 2000 Jul;31(7):871-3 Abstract quote

Common-variable immunodeficiency (CVI) patients develop non-Hodgkin's lymphomas (NHL), mainly B-lineage diffuse large-cell lymphomas (DLCL), with a high relative risk. The molecular pathogenesis of CVI-related NHL (CVI-NHL) is unknown.

Here we aimed at providing a detailed molecular characterization of CVI-NHL. Rearrangements of BCL-6 were detected in two thirds of CVI-NHL cases examined. All 3 CVI-NHL also harbored point mutations of the BCL-6 5' noncoding regions, which constitute a marker of B-cell transit through the germinal center (GC). The number and molecular pattern of BCL-6 mutations in CVI-NHL were similar to that detected in DLCL of immunocompetent hosts and in DLCL arising in other immunodeficiency settings. Microsatellite instability occurred in one CVI-NHL devoid of a BCL-6 rearrangement. All CVI-NHL scored negative for genetic lesions of BCL-2, p53, c-MYC, REL as well as for viral infection by EBV and HHV-8.

Overall, these data indicate that: similarly to other immunodeficiency-related NHL, involvement of BCL6 occurs frequently also in CVI-NHL; and because BCL-6 mutations are acquired by B cells during GC transit, their occurrence in CVI-NHL suggest that these lymphomas are histogenetically related to GC B cells.

PATHOGENESIS CHARACTERIZATION

Decreased immunoglobulin production
Unclear whether it is due to an abnormality intrinsic to the B cells or is secondary to a T-cell abnormality

There is no convincing evidence of any intrinsic B-cell defects but the B cells of the patient with CVI are immature

The B cells may not receive the appropriate T-cell signals during a critical early stage of development as a consequence of a defective production of T-cell cytokines,

May result from a biochemical defect in activation pathways common to both T and B cells, which results in the reduced ability of T and B cells to undergo normal differentiation and produce lymphokines and immunoglobulins

Evidence for a defect in �switch� T cells in patients with immunodeficiency and hyperimmunoglobulinemia M.

Mayer L, Kwan SP, Thompson C, Ko HS, Chiorazzi N, Waldmann T, et al.

N Engl J Med 1986;314:409-13

Increase in the absolute number of suppressor CD8+ T cells possibly affecting the B-cell differentiation at an early stage, at least in a subgroup of patients with CVI

HISTOLOGICAL TYPES CHARACTERIZATION

General

VARIANTS

Skin

Cutaneous granulomas with two clinical presentations in a patient with common variable immunodeficiency.

Ziegler EM, Seung LM, Soltani K, Medenica MM.
J Am Acad Dermatol 1997;37:499-500.

Cutaneous sarcoid-like granulomas in primary immunodeficiency disorders

Levine TS, Price AB, Boyle S, Webster ADB.
Br J Dermatol 1994;130:118-20.

Clonal CD8+ infiltration of the skin in common variable immunodeficiency: A prelymphomatous stage?

Angelo V. Marzano, etal.

J Am Acad Dermatol 2001;44:710-3. Abstract quote

Common variable immunodeficiency is a heterogeneous syndrome characterized by hypogammaglobulinemia and recurrent bacterial infections. Patients with this syndrome also have an increased incidence of autoimmune disease and malignancy, most notably lymphoproliferative disorders. The treatment for common variable immunodeficiency is supported by the use of intravenous infusion of immunoglobulins that allows for control of the disease and avoidance of recurrent opportunistic infections.

This report describes a young patient having common variable immunodeficiency who presented with a clonal CD8+ lymphocytic infiltration of the skin clinically manifesting as a widespread papulonodular eruption and resolving with intravenous immunoglobulin therapy.

We speculate that such a unique cutaneous presentation may represent a prelymphomatous condition because of the development of an autonomous T-suppressor/cytotoxic cell clone, possibly also responsible for the impaired immunoglobulin production.

N Engl J Med 1995;333:431-40.
Ann Intern Med 1993;118:720-30.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

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Commonly Used Terms
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Diagnostic Process
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Surgical Pathology Report
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Special Stains
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Got Path?
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Last Updated 1/5/2004

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Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	CVI
AGE RANGE-MEDIAN	Second or third decade of life

DISEASE ASSOCIATIONS	CHARACTERIZATION
Peripheral T cell lymphoma in a patient with common variable immunodeficiency disease: case report and literature review. Gottesman SR, Haas D, Ladanyi M, Amorosi EL.	Leuk Lymphoma 1999;32:589-95.
Common variable hypogammaglobulinemia complicated by an unusual T-suppressor/cytotoxic cell lymphoma. Durham JC, Stephens DS, Rimland D, Nassar VH, Spira TJ.	Cancer 1987;59:271-6
Common-variable immunodeficiency-related lymphomas associate with mutations and rearrangements of BCL-6: pathogenetic and histogenetic implications. Ariatti C, Vivenza D, Capello D, Migliazza A, Parvis G, Fassone L, Buonaiuto D, Savinelli F, Rossi D, Saglio G, Gaidano G. Department of Medical Sciences, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.	Hum Pathol 2000 Jul;31(7):871-3 Abstract quote Common-variable immunodeficiency (CVI) patients develop non-Hodgkin's lymphomas (NHL), mainly B-lineage diffuse large-cell lymphomas (DLCL), with a high relative risk. The molecular pathogenesis of CVI-related NHL (CVI-NHL) is unknown. Here we aimed at providing a detailed molecular characterization of CVI-NHL. Rearrangements of BCL-6 were detected in two thirds of CVI-NHL cases examined. All 3 CVI-NHL also harbored point mutations of the BCL-6 5' noncoding regions, which constitute a marker of B-cell transit through the germinal center (GC). The number and molecular pattern of BCL-6 mutations in CVI-NHL were similar to that detected in DLCL of immunocompetent hosts and in DLCL arising in other immunodeficiency settings. Microsatellite instability occurred in one CVI-NHL devoid of a BCL-6 rearrangement. All CVI-NHL scored negative for genetic lesions of BCL-2, p53, c-MYC, REL as well as for viral infection by EBV and HHV-8. Overall, these data indicate that: similarly to other immunodeficiency-related NHL, involvement of BCL6 occurs frequently also in CVI-NHL; and because BCL-6 mutations are acquired by B cells during GC transit, their occurrence in CVI-NHL suggest that these lymphomas are histogenetically related to GC B cells.

HISTOLOGICAL TYPES	CHARACTERIZATION
General
VARIANTS
Skin
Cutaneous granulomas with two clinical presentations in a patient with common variable immunodeficiency. Ziegler EM, Seung LM, Soltani K, Medenica MM.	J Am Acad Dermatol 1997;37:499-500.
Cutaneous sarcoid-like granulomas in primary immunodeficiency disorders Levine TS, Price AB, Boyle S, Webster ADB.	Br J Dermatol 1994;130:118-20.
Clonal CD8+ infiltration of the skin in common variable immunodeficiency: A prelymphomatous stage? Angelo V. Marzano, etal.	J Am Acad Dermatol 2001;44:710-3. Abstract quote Common variable immunodeficiency is a heterogeneous syndrome characterized by hypogammaglobulinemia and recurrent bacterial infections. Patients with this syndrome also have an increased incidence of autoimmune disease and malignancy, most notably lymphoproliferative disorders. The treatment for common variable immunodeficiency is supported by the use of intravenous infusion of immunoglobulins that allows for control of the disease and avoidance of recurrent opportunistic infections. This report describes a young patient having common variable immunodeficiency who presented with a clonal CD8+ lymphocytic infiltration of the skin clinically manifesting as a widespread papulonodular eruption and resolving with intravenous immunoglobulin therapy. We speculate that such a unique cutaneous presentation may represent a prelymphomatous condition because of the development of an autonomous T-suppressor/cytotoxic cell clone, possibly also responsible for the impaired immunoglobulin production.