Final Diagnosis -- Epstein-Barr virus related gastritis

DIAGNOSIS:   Intense gastritis with reactive lymphoid infiltrate compatible with Epstein-Barr virus related gastritis.

DISCUSSION:

Epstein-Barr virus induced gastritis is distinctly uncommon with only two case reports found upon search of the Pub Med database, including the unfortunate terminology of "pseudolymphoma" applied to one of the cases (1,2). The clinicopathologic features of each case are summarized (Table 1). Gastrointestinal symptoms as the primary presentation in infectious mononucleosis are extremely uncommon, with most cases presenting with the classic mononucleosis features (e.g. fever, malaise, lymphadenopathy, splenomegaly, etc).

Table 1: Clinicopathologic Features

CASE 1	Kitayama et al, 2000
Age	40
Gender	Male
Clinical Presentation	- Ten day history of pyrexia and diarrhea - Thickened gastric wall with perigastric lymphadenopathy,    splenomegaly
Laboratory Testing	- Leukocytosis with lymphocytosis and atypical lymphocytes. - Positive VCA IgG, IgM - Positive EA and EBNA - Negative hepatitis and CMV serologies.
Histology	- Diffuse atypical lymphoid infiltrate - H. pylori IHC negative - CD20, CD79a positive atypical lymphocytes - EBV (in situ) positive
Outcome	- Symptoms resolved after 25 days. - Disease free for 19 months
CASE 2	Zhang et al, 2003
Age	58
Gender	Male
Clinical Presentation	- Four-day history of malaise, headache, myalgias, chills, anorexia,    nausea, vomiting, diarrhea, lower quadrant abdominal pain.        - Mild splenomegaly, normal hepatobiliary tract, retroperitoneal    lymphadenopathy, diffuse gastric wall thickening.
Laboratory Testing	- Lymphocytosis with atypical lymphocytes, anemia,    thrombocytopenia, elevated liver enzymes. - Positive Monospot test, Elevated VCA IgM, negative VCA IgG,    negative CMV and hepatitis serologies.
Histology	- Mucosal ulceration with severe acute gastritis and diffuse, mixed   transmucosal inflammatory infiltrate (lymphocytes, plasma cells, and   immunoblasts) - Polytypic B and T cells; polyclonal kappa/lambda; - CD20 positive immunoblasts were EBV (in situ) positive; T cells    were negative. - H. pylori IHC negative
Outcome	-Symptoms resolved after 8 days -Disease free for 10 months. -No follow-up studies

Laboratory testing usually demonstrates peripheral blood atypical lymphocytes with variable Monospot positivity. Depending on when testing occurs in relation to disease evolution, EBV viral capsid antigen (VCA) (IgM and/or IgG), EBV early antigen, and/or EBV nuclear antigen (EBNA) may be positive. Liver and/or pancreatic enzymes can be elevated, although not markedly.

On routine histology, a diffuse, mixed, predominately lymphoid infiltrate with scattered immunoblasts is characteristically observed. The infiltrate can be so pronounced and atypical that it can resemble lymphoma (hence the term "pseudolymphoma".) Depending on the evolution of the disease, either CD20 positive B cells (early) or CD3 positive T cells (late) comprise the majority of the lymphoid population, although the overall infiltrate is heterogenous throughout the disease course (2). Kappa and lambda light chain expression is polytypic. In situ hybridization for EBV (e.g. EBER) is usually positive and has been shown to be equivalent to serologic testing. However, given most individuals have latent EBV (prevalence), the detection of EBV by in situ hybridization in individuals with gastritis (incidence) is not diagnostic without clinical correlation (2).

The primary differential diagnostic consideration is lymphoma given that EBV gastritis may present with similar clinical and radiographic findings (i.e. abdominal mass, lymphadenopathy, etc). A heterogenous lymphoid population without light chain restriction or aberrant CD expression supports a benign process. Ultimately, clinicopathologic, flow cytometric, and/or lymphocyte gene rearrangement correlation may be necessary to definitively exclude lymphoma (although reactive conditions may have small clonal lymphocyte populations as well.)

Of interest, the current case demonstrated diffuse lymphoid infiltration of the appendix, a finding that has been previously reported with EBV-induced gastrointestinal pseudo-obstruction (3). Moreover, the presence of the positive ANA with centromeric pattern (4,5) (e.g. Anti-RNP) and ASMA titers (6) is a known association with EBV infection.

FOLLOW-UP:

Subsequent EBV serologies showed positive VCA IgM, equivocal VCA IgG, and negative EBV nuclear antigen (EBNA). These results are consistent with acute EBV infection. In situ hybridization for EBV (EBER) later performed on the liver biopsy demonstrated focal positivity in the mononuclear cells.

REFERENCES:

1. Kitayama Y, Honda S, Sugimura H. Epstein-Barr virus-related gastric pseudolymphoma in infectious mononucleosis. Gastrointest Endosc. 2000 Aug;52(2):290-1
2. Zhang Y, Molot R. Severe gastritis secondary to Epstein-Barr viral infection. Unusual presentation of infectious mononucleosis and associated diffuse lymphoid hyperplasia in gastric mucosa. Arch Pathol Lab Med. 2003 Apr;127(4):478-80.
3. Besnard M, Faure C, Fromont-Hankard G, Ansart-Pirenne H, Peuchmaur M, Cezard JP, Navarro J.Intestinal pseudo-obstruction and acute pandysautonomia associated with Epstein-Barr virus infection. Am J Gastroenterol. 2000 Jan;95(1):280-4.
4. Kojima K, Nagayama R, Hirama S, Maeda T, Takikawa H, Miyake K, Yamanaka M, Shiga J. Epstein-Barr virus infection resembling autoimmune hepatitis with lactate dehydrogenase and alkaline phosphatase anomaly. J Gastroenterol. 1999 Dec;34(6):706-12.
5. Migliorini P, Baldini C, Rocchi V, Bombardieri S. Anti-Sm and anti-RNP antibodies. Autoimmunity. 2005 Feb;38(1):47-54.
6. Garzelli C, Incaprera M, Bazzichi A, Falcone G. Detection of an idiotope on a human monoclonal autoantibody by monoclonal anti-idiotypic antibody and its relationship to Epstein-Barr virus-induced autoimmunity. Autoimmunity. 1992;11(3):171-7.

Contributed by Andrew Walls, MD and Chad Rund, MD