EBV-positive lymphoproliferative disease: a case report

Abstract

Bloody stool with fever may always be considered as inflammatory bowel disease or intestinal tuberculosis. Epstein-Barr virus (EBV) infection is common. But EBV-positive lymphoproliferative disease (EBV⁺-LPD) involvement of gut is pretty rare and is hardly taken into consideration. A 34-year-old woman was admitted to our hospital for bloody stools over one month and fever over one week with multiple black brown nodular erythema on face. With the electronic colonoscope, intestinal tuberculosis was considered firstly, but Crohn’s disease and lymphoma cannot be ruled out. So the patient received diagnostic anti-tuberculosis therapy on Aug. 2^nd, 2012. After 8 months of antituberculosis therapy and drug withdrawal for 4 months, the patient developed symptoms of umbilicus pain accompanied with vomit, diarrhea and hyperpyrexia up to 40.3°C. The discomfort didn’t get complete remission after symptomatic treatment. And on Apr. 20^th, 2015, colonoscopy showed multiple ulcers in colon, so inflammatory bowel disease was considered firstly. As a result, the patient was treated with Mesalazine. However, there was little symptomatic improvement and more black brown nodular erythema occurred on her face. Then on Jun. 11^th, 2015, she underwent colonoscopy again and the immunohistochemical of intestinal tissue suggested EB virus infection. What’s more, we found serum EB virus IgM: - S/CO, serum EB virus IgG: + 12.5 S/CO, blood EBV-DNA: 5.71*10E5/mL (0-500). Furthermore, on Jun. 25^th, 2015, skin biopsy showed (forehead) T lymphocytes hyperplasia and focal necrosis, according with characteristics of EBV related T lymphocyte proliferative disease (EBV⁺T-LPD). Ultimately, we got definitive diagnosis of the patient: 1. EBV⁺-LPD, hydroa vacciniforme-like lymphoma. 2. Multiple ulcers in small intestine and colon: according with EBV⁺-LPD. And she was treated with definitive therapy. This case shows we must consider rare disease for patients accompanied by gastrointestinal symptoms with conventional treatment ineffectively.

Introduction

A majority of of humans are infected with the Epstein-Barr virus (EBV) and the infection persists for life. Most of the infections are chronic and asymptomatic, however, the virus is associated with some life-threatening complications, such as virus-associated hemophagocytic syndrome, interstitial pneumonia, lymphoma and so on [1-3]. EBV-positive lymphoproliferative disease (EBV⁺-LPD) may present with fever, lymphadenopathy, pancytopenia, and hepatosplenomegaly. And these symptoms are mainly due to excessive macrophage activation and hemophagocytosis. What’s more, affected patients always have high levels of EBV DNA in the blood, histological evidence of organ disease, and elevated levels of EBV RNA or viral proteins in affected tissues [4].

We herein report a case that the patient mainly suffered from fever, gastrointestinal symptoms, erythras, and was eventually diagnosed as EBV⁺T-LPD.

Case presentation

A 34-year-old woman was admitted to our hospital for bloody stools and fever on July 26 th, 2012. She complained of bloody stools 8 times accompanied with active borborygmus but without chill, fever, haematemesis, abdominal pain and distension one month ago. Nothing abnormal was detected by anus finger exam in local hospital. After one day, bloody stools stopped without any treatment. Three weeks later, the patient experienced hyperpyrexia up to 39.8°C, and it lasted for one week. The temperature dropped after antibiotics therapy in local hospital. Electronic colonoscope of our hospital showed “multiple ulcers in terminal ileum, ileocecal valve and ascending colon close to ileocecal valve”, and pathology showed “chronic inflammation of (ascending colon) mucous membrane accompanied with exudation of inflammatory necrosis, but no granuloma”. Her stool was yellow and formed, up to three to four times per day when she was admitted to our hospital. She lost 5 Kg of weight within one month. The patient’s previous physical condition was not very good, and she once went through right sublingual gland cyst and sublingual gland resection.

Physical examination

Multiple black brown nodular erythema, Body Temperature: 37.2°C, Pulse: 95/min, Respiratory Rate: 18/min, Blood Pressure: 120/80 mmHg, sober consciousness, weak spiritual condition, no superficial lymph nodes enlargement, no icterus, no abnormal finding in lung and heart, abdomen soft, no tenderness and rebound tenderness, no hepatomegaly and splenomegaly, negative shifting dullness, borborygmus 3/min, no limbs edema, negative nervous system examination.

Laboratory tests

T-SPOT: negative; PPD-test: negative. IgG 1610.0 mg/dL, Antinuclear antibody: +, 1:40. Hb 101 g/L; C-reactive protein (CRP) 8.3 mg/L; ESR 23 mg/L. INR 1.17; APTT 40.9 s; PT 13.6 s. Stool routine + Occult blood test (OB): brown, soft, OB: -. Tumor marker, urine routine, ANCA, bloody biochemistry, HCV, HIV, syphilis, HBV+HBV-DNA: no evidence of abnormality.

Imageological examination

Electrocardiogram: no evdence of abnormality. 2012-07-28 chest CT: a few fibrous foci in left lower lung. 2012-07-20 The total abdomen plain scan CT and enhanced CT (Figure 1A, 1B): incrassated and enhanced bowel wall, accompanied with hemorrhagic change of intestinal tract and thickened disorganized blood vessels, was seen in partial ileocecal junction and lower segment ascending colon. Multiple enlarged lymph nodes lied in posterior peritoneum and mesentery. Spleen enlargement. A little pelvic effusion.

Figure 1.

A, B: 2012-07-20 The total abdomen plain scan CT and enhanced CT: incrassated and enhanced bowel wall, accompanied with hemorrhagic change of intestinal tract and thickened disorganized blood vessels, was seen in partial ileocecal junction and lower segment ascending colon. Multiple enlarged lymph nodes lied in posterior peritoneum and mesentery. Spleen enlargement. A little pelvic effusion. C, D: 2015-05-09 Small intestine CT enterolysis: multiple segmental inflammations in ascending colon and ileum, Crohn’s disease considered firstly, no mesenteric abscess or sinus tract, splenauxe, and mild hepatomegaly.

2012-07-02 Colonoscopy (Figure 2A): ulcers covered by white fur in terminal ileum and ileocecal valve, multiple ulcers covered by white fur with clear brittle-ductile border in ascending colon close to ileocecal valve. Pathological examination (Figure 3A): (initial position of ascending colon) moderate chronic mucosal inflammation accompanied with obvious inflammatory necrosis exudation, without granuloma.

Figure 2.

A: 2012-07-02 Colonoscopy: ulcers covered by white fur in terminal ileum and ileocecal valve, multiple ulcers covered by white fur with clear brittle-ductile border in ascending colon close to ileocecal valve. B: 2012-08-02 Capsule endoscopy: multiple small ulcers in terminal ileum and ileocecal valve. C: 2012-12-20 Colonoscopy: ulcer was disappeared, but mucous hyperemia and patchy erosion and inflammation in ileocecal valve was seen. D: 2014-04-09 Colonoscopy: multiple spotted ulcers surrounded by congested mucosa in colorectum and an about 1*1.2 cm ulcer covered by white fur and surrounded by dam-like raised mucosa in initial position of ascending colon. E: 2015-04-20 Colonoscopy: multiple ulcers in colon, inflammatory bowel disease considered firstly, congestive mucosa in ileocecal junction and ileocecal valve, multiple deep and big ulcers covered with white fur and congestive oedenatous anabrotic mucosa in ascending colon and transverse colon, multiple aphthae surrounded by normal mucosa in descending colon and sigmoid colon, congestive anabrotic mucosa in rectum. F: 2015-06-11 Colonoscopy: multiple ulcers in colon, Crohn’s disease considered firstly (congestive swollen ileocecal valve, multiple sporadic erosions and ulcers in whole colon).

Figure 3.

A: 2012-07-02 Colonoscopy pathological: (initial position of ascending colon) moderate chronic mucosal inflammation accompanied with obvious inflammatory necrosis exudation, without granuloma. B: 2014-04-09 Colonoscopy pathological: chronic inflammation in initial position of ascending colon and obvious inflammatory necrosis exudation. C: 2015-04-20 Colonoscopy pathology: chronic mucosal inflammation (ascending colon) accompanied with lots of inflammatory cells infiltration and erosion. D: 2015-06-11 Colonoscopy pathology: (ileocecal junction and ascending colon). It showed inflammatory changes of mucosa. And it showed normal mucous glands and intestinal epithelial differentiation, segmental inflammatory changes, lots of lymphocytes and lymphangiectasia in lamina propria in partial region, no ulcer or granuloma. CD2(+), CD3(+), CD4(+), CD5(+), CD7(+), CD8(+), CD10(-), CD20(+), CD21(minority +), CD23(minority +), CD56(+), EBER(+), Ki-67(+, low), Bcl-6(-).

2012-08-02 Capsule endoscopy (Figure 2B): multiple small ulcers in terminal ileum and ileocecal valve.

Primary diagnosis and treatment

Intestinal tuberculosis was considered firstly, and Crohn’s disease and lymphoma cannot be ruled out. Nutrition supplement such as TPF-T and Novamin and fluid infusion were done after the patient was admitted. The patient received diagnostic anti-tuberculosis therapy that concluded Rifampin, Isoniazid and Ethambutol on Aug. 2^nd, 2012. She had recurrent a little hemafecia among the following four months of diagnostic anti-tuberculosis therapy. On Dec. 20^th, 2012, she had colonoscopy examination (Figure 2C). And it showed that ulcer was disappeared, but mucous hyperemia and patchy erosion and inflammation in ileocecal valve was seen.

Disease progression

The patient was admitted to local hospital on Aug. 21^st, 2013 for two times of a little melena five days ago. She stopped antituberculosis therapy that lasted 8 months and taking mesalazine in Apr. 2013. The gastroscopy showed chronic non-atrophic gastritis, and the colonoscopy showed ileocecal valve inflammation and sigmoid rectum inflammation. She got better after symptomatic treatment. Apr. 9^th, 2014, colonoscopy (Figure 2D) showed that there were multiple spotted ulcers surrounded by congested mucosa in colorectum and an about 1*1.2 cm ulcer covered by white fur and surrounded by dam-like raised mucosa in initial position of ascending colon, and pathology (Figure 3B) showed chronic inflammation in initial position of ascending colon and obvious inflammatory necrosis exudation.

In Apr. 2015, the patient returned to local hospital for umbilicus pain for over one month accompanied with vomit and diarrhea and fever up to 40.3°C. CRP went up then went down after treatment, but ESR sustained high value. Apr. 20^th, 2015, colonoscopy (Figure 2E) showed multiple ulcers in colon, inflammatory bowel disease considered firstly, congestive mucosa in ileocecal junction and ileocecal valve, multiple deep and big ulcers covered with white fur and congestive oedenatous anabrotic mucosa in ascending colon and transverse colon, multiple aphthae surrounded by normal mucosa in descending colon and sigmoid colon, congestive anabrotic mucosa in rectum. Colonoscopy pathology (Figure 3C) showed chronic mucosal inflammation (ascending colon) accompanied with lots of inflammatory cells infiltration and erosion.

Mesalazine dose was increased to 1.0 mg, three times a day. May 9^th, 2015, small intestine CT enterolysis (Figure 1C, 1D) showed multiple segmental inflammations in ascending colon and ileum, Crohn’s disease considered firstly, no mesenteric abscess or sinus tract, splenauxe, and mild hepatomegaly.

On May 27^th, 2015, the patient was admitted to local hospital again for recurrent abdominal pain for over 2 months accompanied with vomit and diarrhea, and fever for two days up to 38.9°C. The erythrocyte spin resonance (ESR) was 23 mm/h, and CRP was 91.9 mm/L. She was treated with anti-inflammation and fluid infusion. May 27^th, 2015, there were lots of black brown nodular erythema in her face (Figure 4A), and it remitted after intestinal symptom appeared. The patient received Aloson ointment, 0.03% Tacrolimus, Loratadine and Gentamicin on Feb. 19^th, 2014, and Isotretinoin and Polymyxin B on Dec. 3^rd, 2014, but the symptom didn’t remit.

Figure 4.

A: 2015-05-27 There were lots of black brown nodular erythema in her face, and it remitted after intestinal symptom appeared. B: 2015-06-25 skin biopsy: (forehead) T lymphocytes hyperplasia and focal necrosis, according with characteristics of EBV related T lymphocyte proliferative disease (EBV⁺-LPD): erosion on the skin surface, lots of abnormal lymphocyte in dermis and some in epidermis.

Jun. 11^th, 2015, colonoscopy (Figure 2F) showed multiple ulcers in colon, Crohn’s disease considered firstly (congestive swollen ileocecal valve, multiple sporadic erosions and ulcers in whole colon). Colonoscopy pathology (Figure 3D) diagnosis was (ileocecal junction and ascending colon) inflammatory changes of mucosa. It showed normal mucous glands and intestinal epithelial differentiation, segmental inflammatory changes, lots of lymphocytes and lymphangiectasia in lamina propria in partial region, no ulcer or granuloma. CD2(+), CD3(+), CD4(+), CD5(+), CD7(+), CD8(+), CD10(-), CD20(+), CD21(minority +), CD23(minority +), CD56(+), EBER(+), Ki-67(+, low), Bcl-6(-).

Serum EB virus IgM: - S/CO, serum EB virus IgG: + 12.5 S/CO, blood EBV-DNA: 5.71*10E5/mL (0-500). On Jun. 25^th, 2015, skin biopsy (Figure 4B) showed (forehead) T lymphocytes hyperplasia and focal necrosis, according with characteristics of EBV related T lymphocyte proliferative disease (EBV⁺-LPD): erosion on the skin surface, lots of abnormal lymphocyte in dermis and some in epidermis. Immunohistochemical: CD2(+), CD3(+), CD4(+), CD5(+), CD7(+), CD8(+), CD20(-), CD56(-), TIA-1(+), Granzme B(+) EBER(+), Ki-67(+, 20%). Gene rearrangement of TCRγ: Vγ1-8(-), Vγ9(+), Vγ10(+), Vγ11(-).

Definitive diagnosis

EBV related T lymphocyte proliferative disease (EBV⁺-LPD), hydroa vacciniforme-like lymphoma.

Multiple ulcers in small intestine and colon: according with EBV⁺-LPD.

Discussion

Chronic active Epstein-Barr virus (CAEBV) disease has been defined as a systemic EBV-positive lymphoproliferative disease (EBV⁺-LPD) characterized by fever, lymphadenopathy, and splenomegaly developing after primary virus infection in patients without known immunodeficiency. There are two types of EBV-associated lymphoproliferative diseases (EBV⁺-LPD): CAEBV B-cell type and CAEBV T-cell/NK cell types. Subtypes of CAEBV B-cell type include EBV⁺ large B-cell lymphoma of the elderly (senile EBV LPD) and lymphomatoid granulomatosis. Subtypes of CAEBV T-cell/NK cell types include HV, HV-like lymphoma, severe mosquito bite allergy and systemic EBV⁺ T-cell LPD of childhood. The disease has a strong racial predisposition, with most cases occurring in Asian and Latin American countries.

The diagnostic criteria which was first proposed by Straus [5] and revised by Kimura [4] include the following terms: (i) begins as a primary EBV infection or is associated with markedly abnormal EBV antibody titers (e.g. anti-EBV viral capsid antigen IgG ≥ 5120, anti-EBV early-antigen IgG ≥ 640, or anti-EBNA < 2); (ii) histological evidence of major organ involvement such as interstitial pneumonia, hypoplasia of the bone marrow, uveitis, lymphadenitis, persistent hepatitis, or splenomegaly; and (iii) increased EBV RNA or proteins in affected tissues or increased levels of EBV in the peripheral blood.

A number of therapies have been tried for CAEBV including antiviral agents (acyclovir, ganciclovir), immunomodulators (IFN-α, IL-2), chemotherapy (etoposide, corticosteroids), cyclosporine, EBV-specific cytotoxic T cells (CTLs), and recently more promising results of hematopoietic cell transplantation [6,7]. However, the long-term prognosis of the disease is still unsatisfactory because of many complications.

While CAEBV was first described as a persistent EBV infection targeting B cells, over the years the syndrome has been primarily associated with EBV infection of T cells and less often NK cells [4]. The term T/NK cell CAEBV encompasses a very broad spectrum of diseases, including a systemic form which may be polyclonal, fulminant and clonal. The 2008 WHO classification has recognized the following disease entities that are considered neoplasms: systemic EBV-positive T-cell LPD of childhood (a clonal T-cell LPD) and HV-like T-cell lymphoma. Patients with T-cell CAEBV often presented with high fever, lymphadenopathy, hepatosplenomegaly, high titer of EBV-specific antibodies, and had rapid progression of their disease. A study reported that the 5-year survival rate of patients with T-cell CAEBV was 59% [8].

A study from Peru presented features of HV-like T-cell lymphoma including infiltrative growth pattern, often aberrant T-cell phenotype, clonal rearrangement of TCR genes, and poor clinical outcome [9]. The mean age of patients in Peru was 11 years (range 5-17 years). Lesions most commonly involved sun-exposed areas (face and upper limbs). Lesions often showed edema, papules, blisters, crusts, ulcers, and healed as vacciniforme scars. In this study, the 2-year survival rate was 43% and deaths were due to sepsis, liver failure, malignancy, or hemophagocytic syndrome.

The criteria for the distinction of HV from HV-like T-cell lymphoma have not been clearly delineated. EBV and T-cell clonality were found in both types of cases. However, cases of HV lacking clonal rearrangement of TCR genes appear to have a more benign clinical course [10]. And the entity of HV-like lymphoma as included in the WHO classification stipulates an EBV-positive clonal proliferation.

In our case, compared with other cases which had been reported, the clinical manifestations were atypical and progression of the disease was relatively slow. As a result, the process of diagnosis and therapy was lengthy before we got a definite diagnose.

In conclusion, this case reminds us that we must consider rare diseases for patients accompanied by gastrointestinal symptoms with conventional treatment ineffectively. EBV⁺-LPD is infrequent in clinic, and its involvement of gut is more rare. Its differential diagnosis from inflammatory bowel disease and intestinal tuberculosis through clinical manifestation is difficult. So making a definite diagnosis largely depends on pathologic findings and laboratory examinations.

Disclosure of conflict of interest

None.