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Primary intestinal intraepithelial natural killer-like T-cell lymphoma: case report of a distinct clinicopathologic entity.

The diagnosis of intestinal T-cell lymphoma poses a diagnostic dilemma. Intraepithelial T-cell infiltration is a normal immune phenomenon. An increase in intraepithelial lymphocytes accompanied by villous atrophy and crypt hyperplasia may represent celiac disease or may represent lymphoma. (1,2) In addition, T-cell lymphoma is frequently associated with celiac disease and may also show infiltration by nonneoplastic inflammatory cells, adding complexity to the diagnosis. (3,4) Refractory sprue (celiac disease without response to strict gluten-free diet) is particularly difficult to distinguish from T-cell lymphoma as it also shows aberrant immunophenotype and monoclonal T-cell receptor (TCR) [gamma]-chain gene rearrangement. (1,5-7) Morphologically, intestinal T-cell lymphoma may show a monomorphic small cell morphology without tumor mass formation (2,8); those cases are particularly problematic for a definitive diagnosis.

Primary intestinal T-cell lymphoma is now designated enteropathy-type T-cell lymphoma in the World Health Organization classification and intraepithelial T cells are postulated as the cells of origin. (9) Intestinal intraepithelial lymphocytes represent one of the largest nonorganized lymphoid populations in the human body; they are composed of heterogenous subsets with diverse ontogeny and phenotype. (1,10) These subsets may represent T cells or natural killer (NK) cells and neoplastic counterparts of each may arise. (2,3,11,12) In addition, there are systemic T-cell or NK-cell lymphomas (such as [gamma][delta] T-cell lymphoma and extranodal NK/T-cell lymphoma, nasal type) that may involve the intestine and make the differential diagnosis even more complicated. (2,3,11,12) Enteropathy-type T-cell lymphoma is a highly aggressive disease with a high mortality rate and a clinical course that may be complicated by intestinal obstruction, perforation, and/or peritonitis. (1,2,9) Therefore, in spite of its low incidence, accounting only for less than 5% of intestinal lymphomas, it is important to recognize this entity.

We report a case of intestinal intraepithelial NK-like T-cell lymphoma showing a unique immunophenotype to exemplify the heterogeneity of intraepithelial T cells and the role of immunophenotyping in the differential diagnosis.


A 72-year-old African American man presented with a 6-month history of diarrhea of unknown etiology. The diarrhea was watery with no melena or hematochezia. He had nausea and vomiting but no hematemesis. He had associated left lower quadrant pain, relieved with flatulence. His abdominal examination was notable for distention and mild diffuse tenderness to palpation. He had normal bowel sounds in all 4 quadrants, no shifting dullness, no caput medusa, no rebound tenderness, no referred tenderness, and no guarding. His stool was guaiac negative.

In the 6 months prior to presentation, the patient had a thorough workup of his diarrhea, including fecal leukocytes, stool culture, examination for parasites and ova, and tissue transglutaminase, but all results were negative. A gluten-free diet failed to improve his condition.


The first endoscopic examination showed no gross abnormalities of the duodenum and only paleness of the colon and a solitary small polyp. A second endoscopy was performed 4 weeks after the first examination. The duodenum showed small areas of erythema and blunted villi. The jejunum revealed nodularity and erythema, but no gross abnormality was noted in the stomach. From the biopsies, a diagnosis of intestinal T-cell lymphoma was finally established. The patient was admitted to the inpatient hospice, where he died 1 day after admission.


The first duodenal biopsy showed extensive lymphoid infiltration of the lamina propria (Figure 1, A). The lymphoid cells were monomorphic small to medium-sized cells. Intraepithelial lymphoid infiltrates were seen in a small number of intestinal crypts, but a prominent lymphoepithelial lesion was not demonstrated. Immunohistochemical stains revealed positive CD3 and CD8 reactions but negative CD4 reactions (Figure 1, B through D) as well as negative CD20 reaction on the lymphoid cells. The colonic biopsy showed similar morphologic features and immunophenotype ([CD4.sup.-][CD8.sup.+]).


The second small intestinal biopsy showed marked histologic progression as compared with the first biopsy. There was extensive infiltration of the lamina propria by monomorphic small- to medium-sized lymphocytes with prominent intraepithelial infiltrates and partial destruction of the crypts (lymphoepithelial lesions) (Figure 1, E). There were also admixed plasma cells and eosinophils in the lamina propria. The submucosa was also involved by the lymphoid infiltrate. Villous atrophy was present. The gastric biopsy also showed extensive lymphoid infiltration in the mucosa with less prominent intraepithelial infiltration.

Immunohistochemical staining of the second small intestinal biopsy showed that all lymphoid cells were CD3 positive (Figure 1, F). In situ hybridization for Epstein-Barr virus-encoded RNA revealed no reaction with the lymphoid cells. Immunohistochemical stains performed at the National Institutes of Health revealed that the tumor cells were positive for CD3, CD8, CD56, T-cell intracellular antigen 1 (TIA-1), and [beta]F1 (weak) and were negative for CD4 and CD5. No immunohistochemical stains were performed on the gastric biopsy.

Analysis of the duodenal biopsy with a 4-color flow cytometer (Cytomics FC500, Beckman Coulter, Fullerton, Calif) demonstrated an abnormal T-cell population that expressed 99% CD2, 4% CD3, 100% cytoplasmic CD3, 4% CD4, 2% CD5, 99% CD7, 98% CD8, 2% CD16, 2% CD25, 98% CD56, 2% CD57, and 94% CD103 positive cells (Figure 2, A through F). T-cell receptor [gamma]-chain gene rearrangement studies were performed on formalin-fixed, paraffin-embedded biopsy material from the small intestine. The technique we used was polymerase chain reaction followed by capillary electrophoresis. These studies were positive for a monoclonal TCR gene rearrangement.


A diagnosis of intestinal T-cell lymphoma is difficult when the tumor cells show no prominent atypia and are admixed with plasma cells and eosinophils. An intraepithelial lymphoid infiltration is not an indication of malignancy as it is a normal immunologic response and it is frequently seen in celiac disease and refractory sprue. These nonneoplastic cases may have aberrant immunophenotype or even monoclonality by TCR gene rearrangement analysis (10) but are usually clinically indolent with long survival.

Celiac disease is characterized by villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes of the small intestine. The intraepithelial lymphocytes gradually lose the subset of CD8-positive cells and a subset of double-negative ([CD4.sup.-][CD8.sup.-]) cells increases. (1) Clinically, celiac disease patients have gluten-associated malabsorption. When patients with celiac disease become unresponsive to a gluten-free diet, it is termed refractory celiac disease or refractory sprue. Histologically, patients with re fractory sprue show further increases in intraepithelial lymphoid infiltration. Immunophenotypically, the intraepithelial lymphocytes are typically negative for CD3, CD4, CD8, and TCR protein but are positive for cytoplasmic CD3. (1,5-7) A minority of cases may show a [CD8.sup.+] [CD56.sup.+] population. (1) More importantly, these lymphocytes start to show a monoclonal pattern as demonstrated by TCR gene rearrangement. (1,5-7) Therefore, refractory sprue is considered the transitional stage between celiac disease and enteropathy-type T-cell lymphoma. (1,13,14)

The current case showed rapid progression of intestinal lesions both grossly and histologically within 4 weeks. The small intestinal biopsies revealed extensive lymphoid infiltration of the lamina propria with extension to the submucosa and prominent intraepithelial infiltration with partial destruction of the crypt epithelium. An aberrant immunophenotype ([CD3.sup.-], cytoplasmic [CD3.sup.+], [CD4.sup.-], [CD8.sup.+], [CD5.sup.-], [CD7.sup.+], [CD16.sup.-], [CD56.sup.+], [CD57.sup.-], [CD103.sup.+], [TIA-1.sup.+], and [beta][F1.sup.+]) was demonstrated by immunohistochemistry and flow cytometry. Monoclonality was documented by TCR gene rearrangement analysis. Finally, the patient died within 6 months after disease onset. Therefore, the diagnosis of malignancy appears to be indisputable.

The presence of lymphoepithelial lesion in this patient may suggest the diagnosis of extranodal marginal zone B-cell lymphoma, but the T-cell immunophenotype excludes this entity. The positive CD56, cytoplasmic CD3, and TIA-1 immunostaining may raise the possibility of extranodal NK/T-cell lymphoma involving the gastrointestinal tract. This lymphoma usually shows an angiocentric and angiodestructive growth pattern, which is not demonstrated in this case. (9) Furthermore, the presence of monoclonal TCR gene rearrangement and the negative Epstein-Barr virus-encoded RNA stain exclude this diagnosis. (11)

This immunophenotype is characteristic of NK-like T-cell lymphoma frequently seen secondary to hepatosplenic T-cell lymphoma. (11) However, [gamma][delta] T-cell lymphoma is usually [CD3.sup.+], [CD4.sup.-], [CD8.sup.-], [CD103.sup.-], which is not consistent with the immunophenotype of the current case. Therefore, it appears that this is a primary intestinal intraepithelial NK-like T-cell lymphoma as defined by the presence of CD103. (1,15)

A case similar to ours has been reported by Yuan et al. (4) In their case, the tumor cells expressed cytoplasmic CD3, CD7, CD16, CD56, and CD103 but not CD2, CD3, CD4, CD5, CD8, TIA-1, TCR[alpha][beta], and TCR[gamma][beta]. Monoclonal TCR gene rearrangement was demonstrated, but Epstein-Barr virus-encoded RNA stain was negative. Clinically, this patient also had no gluten-sensitive enteropathy.

Intestinal intraepithelial lymphocytes are composed of heterogeneous subsets. Most studies divide them into 2 subsets. (1,4,5) Most are [CD3.sup.+], [CD4.sup.-], [CD8.sup.+], [CD5.sup.-], [CD103.sup.+] cytotoxic T cells that use the [alpha][beta] T-cell receptor. A minority population (10%-15%) is [CD3.sup.+], [CD4.sup.-], [CD8.sup.-], [CD103.sup.+] and uses the TCR[gamma][delta]. In addition, there is a third population consisting of [CD56.sup.+] intraepithelial lymphocytes, which is an oligoclonal population and virtually undetectable in normal intestinal mucosa. (1) Eiras et al (15)fc have identified a fourth population, which is [CD3.sup.-][CD7.sup.+][CD56.sup.+]. This population is reduced in celiac disease and increased in intraepithelial T-cell lymphoma. (4,15)

The immunophenotype of the case reported by Yuan et al (4) is essentially the same as this newly identified intraepithelial lymphoid population. Our case differs from their case in the demonstration of CD8 and [beta]F1 markers. The clinical significance of this difference is unclear at this time, but it appears that our case represents a more mature stage showing cytotoxic T-cell type differentiation.

Chott et al (12) reported a series of 15 cases of [CD56.sup.+] intestinal T-cell lymphoma, most of which showed an immunophenotype of [[beta]F1.sup.+], cytoplasmic [CD3.sup.+], [CD4.sup.-], [CD5.sup.-], [CD8.sup.+], [CD56.sup.+], [CD57.sup.-], [TIA-1.sup.+] with a monoclonal TCR [gamma]-chain gene rearrangement. Interestingly, the [CD56.sup.+] cases were associated with a monomorphic small- to mediumsized cytology, whereas the [CD56.sup.-] cases were mainly composed of pleomorphic medium and large cells. Clinically, 8 cases of [CD56.sup.+] cases were associated with enteropathy and 7 cases were not. The 1 [CD56.sup.+] case showing CD103 positivity was also not associated with enteropathy. Among the 3 cases that showed [CD56.sup.+] and [CD103.sup.-], 2 were associated with enteropathy. This immunophenotype is essentially identical to our case, except that no CD7 was tested and the absence of surface CD3 was not identifiable in their immunohistochemical study. On the other hand, our case demonstrating the characteristic surface [CD3.sup.-] [CD7.sup.+] [CD56.sup.+] immunophenotype is consistent with the recently identified subset of intestinal intraepithelial lymphocytes. (15)

Two recent studies further demonstrated that the [CD56.sup.+] monomorphic lymphoma is distinguished from the [CD56.sup.-] pleomorphic lymphoma in HLA genotype and cytogenetic aberrations. (16,17) The former shows an HLA-DQB1 genotype pattern resembling that of normal Caucasian population, whereas the latter shares the HLA-DQB1 genotype with celiac disease. (16) In addition, the [CD56.sup.+] monomorphic lymphoma cases reveal frequent MYC oncogene locus gain and rare gain of chromosomes 1q and 5q, whereas the [CD56.sup.-] pleomorphic lymphoma cases show the opposite trend.

It appears that intestinal intraepithelial T-cell lymphoma is a heterogeneous group, including mainly enteropathy-type T-cell lymphoma with a minority being nonenteropathic. (4,12,16,17) The nonenteropathic variant expresses an immunophenotype distinguishing from the major immunophenotype of enteropathy-type T-cell lymphoma ([CD3.sup.+] [CD5.sup.-][CD7.sup.+][CD8.sup.-/+][CD4.sup.-][CD56.sup.-][CD103.sup.+]) (8) and has a characteristic morphologic pattern (monomorphic small cells vs pleomorphic large cells) as well as a distinct cytogenetic composition. Therefore, the nonenteropathic variant should be separated as a distinct clinicopathologic entity.

Because intestinal T-cell lymphoma includes such a diversified group of tumors and there are nonneoplastic conditions that may mimic this lymphoma, a large panel of monoclonal antibodies should be used for an accurate diagnosis. In addition to all the major T-cell markers (CD3, CD4, CD5, CD7, CD8), the intraepithelial T-cell marker (CD103), the NK-cell markers (CD16, CD56, CD57), and cytotoxic granule associated proteins (TIA-1, granzyme B, perforin) should be included. Furthermore, the expression of CD30 (6) and p53 (18) is reported to predict the transformation of refractory sprue to lymphoma or predict a poor prognosis of a lymphoma case and thus they should also be considered for inclusion in the antibody panel of selective cases. Flow cytometry is recommended for immunophenotyping because a large panel of monoclonal antibodies can be used to study a small specimen with the 4-to 5-color flow cytometer. Flow cytometry can also distinguish cytoplasmic from surface CD3, which is important for differential diagnosis.

We wish to thank Elaine S. Jaffe, MD, for her expert opinion on the diagnosis of this case.

Accepted for publication June 5, 2008.


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(12.) Chott A, Haedicke W, Mosberger I, et al. Most [CD56.sup.+] intestinal lymphomas are [CD8.sup.+] [CD5.sup.-] T-cell lymphomas of monomorphic small to medium size histology. Am J Pathol. 1998;153:1483-1490.

(13.) Cerf-Bensussan N, Brausse, Cellier C. From hyperplasia to T cell lymphoma. Gut. 2000;51:304-305.

(14.) Farstad IN, Lundin KEA. Gastrointestinal intraepithelial lymphocytes and T cell lymphomas. Gut. 2003;52:163-164.

(15.) Eiras P, Leon F, Camarero C, et al. Intestinal intraepithelial lymphocytes contain a CD3- CD7+ subset expressing natural killer markers and a singular pattern of adhesion molecules. Scand J Immunol. 2000;52:1-6.

(16.) Deleeuw RJ, Zetti A, Klinker E, et al. Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes. Gastroenterology. 2007;132:1902-1911.

(17.) Baumgartner AK, Zetti A, Chott A, et al. High frequency of genetic aberrations in enteropathy-type T-cell lymphoma. Lab Invest. 2003;83:1509-1516.

(18.) Murray A, Cuevas EC, Jones DB, et al. Study of the immunohistochemistry and T cell clonality of enteropathy-associated T cell lymphoma. Am J Pathol. 1995;146:509-519.

From the Departments of Pathology (Drs Muram-Zborovski and Sun) and Medicine (Dr Loeb), University of Colorado School of Medicine, Denver; and the Pathology and Laboratory Medicine Service, VA Medical Center, Eastern Colorado Health Care System, Denver (Dr Sun).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Tsieh Sun, MD, Pathology and Laboratory Medicine Service, VA Medical Center, Eastern Colorado Health Care System, 1055 Clermont St, Denver, CO 80220 (e-mail:
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Author:Muram-Zborovski, Talia; Loeb, Danielle; Sun, Tsieh
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Case study
Geographic Code:1USA
Date:Jan 1, 2009
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