Hematopathology Diagnoses Too Easy to Miss!
Marsha Kinney, James Cook and Steven Swerdlow
Case 13: The Quiz Case
Diagnosis: Enteropathy-associated T-cell lymphoma
Case history: 60 year old male with nausea, pain, celiac sprue and lesions
in his stomach and small intestine. Gastric ulcer was biopsied. Following his diagnosis, the patient
was treated with CHOP chemotherapy; however, he expired after a short course and after he was discovered
to have a metastatic squamous cell carcinoma of the lung.
Histopathology : Gastric mucosal infiltrate with epitheliotropism composed
of large, occasionally pleomorphic cells. Also neutrophils, some plasma cells and lymphocytes present.
Flow cytometric immunophenotypic studies: None performed.
Paraffin section immunohistochemistry:
- CD20 – Rare positive small cells, abnormal cells negative.
- CD3 – Abnormal cells positive.
- CD5 – Few positive cells, abnormal cells negative (ie, abnormal
T-cell or natural killer cell phenotype!)
- CD4 – Abnormal cells negative
- CD8 – Most abnormal cells positive.
- TIA-1 – Many abnormal cells positive.
- Granzyme B – Many abnormal cells positive.
- CD56 – Most abnormal cells positive.
- Other stains were as follows: CD7 positive on abnormal cells,
anti-kappa and lambda showed a few polyclonal plasma cells, bcl-2 mostly negative on abnormal cells,
bcl-6 and CD10 negative on abnormal cells, CD30 and ALK1 negative, H. pylori negative.
Genotypic & Cytogenetic studies: None performed.
Diagnostic pathway: The atypical infiltrate in these biopsies suggests the
diagnosis of a definite neoplasm that is composed of cells that are too large and associated with too
many mitotic figures to represent a MALT lymphoma, in spite of the epitheliotropism that is clearly
present. The patient's history should raise the question of an enteropathy associated T-cell lymphoma.
The phenotype suggests an "aberrant" T-cell or a natural killer cell phenotype and excludes one of the
large B-cell lymphomas (or an epithelial neoplasm). The diagnosis of a T-cell lymphoma of
enteropathy-associated type was rendered here, knowing that the patient had celiac disease, having a
compatible histopathology including the epitheliotropism, and knowing that enteropathy type T-cell
lymphomas are typically CD5 negative. A minority of cases are reported to be CD56 positive. These cases
are designated as being of "type II" and have been described as being of monomorphic type. 
They are considered to have either less of an association with celiac disease and its risk factors or no
association, although they do share the most characteristic cytogenetic abnormalities. If there were any
concern for a natural killer cell neoplasm, this would be a very appropriate situation to perform
genotypic studies using DNA from the paraffin embedded material and PCR looking for a clonal T-cell
receptor gamma chain gene rearrangement.
This case illustrates the following:
- Paying attention to the clinical history goes a long way since
enteropathy-associated T-cell lymphoma frequently arises in adults with celiac disease.
- Not everything in the stomach is a MALT lymphoma or even a
- Conversely, enteropathy-associated T-cell lymphomas are most
common in the small intestine but can very rarely involve the stomach.
- One of major differences between the WHO (and REAL)
classifications and those that preceded it is the recognition of a group of aggressive extranodal
cytotoxic T-cell and natural killer cell lymphomas (TIA-1 and granzyme B positive).
- Diagnosing lymphomas in 2009 is best accomplished by
integrating histopathologic findings with the results of appropriately selected ancillary studies.
- Don't be overly influenced by any single piece of information.
Just because this was a gastric biopsy didn't mean it had to be one of the lymphomas you usually
associate with the stomach. Also beware, not all lymphomas in patients with celiac disease are of this
- Be aware not only of the classical features for the lymphomas
you need to diagnose, but also know what "exceptions" are allowable. For example, it is acceptable to
diagnose CD56+ enteropathy associated T-cell lymphomas; however, the finding of TdT expression would be
totally unacceptable. Know that there is current interest in considering the CD56+ monomorphic cases as
a distinct subtype of EATL. 
- While we try to be as certain as possible about all of our
diagnoses, sometimes we do need to deal with some degree of uncertainty in diagnostic hematopathology.
- Knowing the clinical implications of the diagnoses you render
makes you a much more useful consultant to your clinical colleagues. It is also useful to understand the
implications of your diagnoses to avoid undue mental anguish. If you cannot decide between two diagnoses
and their treatment and prognosis are similar enough, it may not be worth losing lots of sleep over your
decision (and then making other errors due to fatigue).
Extranodal cytotoxic T-cell and natural killer cell lymphomas: The subject of the extranodal
cytotoxic T-cell and natural killer cell lymphomas was briefly reviewed in the handout for case
Enteropathy-associated T-cell lymphoma: Enteropathy-associated T-cell lymphoma (EATL, aka enteropathy
type T-cell lymphoma) occurs in adults, often with a history of celiac disease, who present with
It has also been described in post-transplantation patients.
Radiologic procedures demonstrate small bowel abnormalities with or without a major mass lesion. Most
typically, EATL arises in the jejunum. Extraintestinal involvement also occurs with common involvement
of mesenteric lymph nodes.  Gastric involvement has been described but is very
rare.  Recognition is important because these are very aggressive even when treated
appropriately.  It should also be recognized that patients with celiac disease also have an
increased risk for other lymphomas as well. 
Histopathology: EATL demonstrates small bowel infiltration by a cytologically heterogeneous
proliferation that includes varying numbers of small, medium and large lymphoid cells although, in most
cases, small cells do not predominate.
Biopsies with predominantly small cells may be
confused with indolent MALT lymphomas. Ulcerated and inflamed lesions may be present and biopsies in
these areas may not be clearly neoplastic-appearing. Some of these lesions may fulfill the criteria for
what has been called "ulcerative jejunitis". Ulcerative jejunitis is an ulcerated polymorphous lesion
that used to be considered a benign complication of celiac disease; however the lesions are clonal and at
least most lesions are now considered neoplastic. Some consider these to be a part of refactory celiac
disease-II (RCD with aberrant phenotype). The 2008 WHO monograph discusses two types of refractory
celiac disease – one that is polyclonal and where the intraepithelial lymphocytes have a normal phenotype
and another that is monoclonal and where the intraepithelial lymphocytes have an abnormal CD8 negative
phenotype. The latter cases, that also can have chromosomal abnormalities are considered as
"intraepithelial T-cell lymphoma or alternatively, EATL in
 EATL was originally recognized as "malignant histiocytosis of the intestine"
because of the numerous admixed lysozyme positive macrophages/histiocytes present. Intravascular tumor
cells are frequently seen but not usually angioinvasion or necrosis. The adjacent bowel often, but not
invariably, demonstrates villous atrophy consistent with celiac disease. There may be striking
epitheliotropism. The CD56+ cases are described as usually being composed of medium-sized round cells
often with striking intraepithelial infiltration and without admixed inflammatory cells (type II EATL).
Immunophenotype: Immunophenotypic studies, most of which can be performed on paraffin embedded tissue
sections, are important in diagnosing EATL, especially in problematic cases.
demonstrate an "aberrant" cytotoxic T-cell phenotype. Pan-T-cell markers are usually expressed except
for CD5. Most are CD4 and CD8 negative (most of remaining cases are CD8 positive). Most express the
-T-cell receptor rather than the -T-cell receptor although some describe
loss of beta chain expression. CD103 is expressed, a feature characteristic of intraepithelial T-cells
(and hairy cell leukemia). The cells express cytotoxic markers such as TIA-1 and granzyme B. A minority
express the NK-associated CD56 antigen (N-CAM) and are CD8+. These latter cases have been reported to
have a distinct morphologic appearance with a predominance of monomorphic medium sized cells.
Some cases are CD30/Ki-1 positive. Many of these antigens can be detected in paraffin embedded
tissue sections, with the major exception being CD103. The marked phenotypic variation that is present
between cases is not considered particularly important. For example, cases derived from T cells
expressing the -T-cell receptor are not currently considered distinct from those
expressing the -T-cell receptor. With the current suggestion that intestinal gamma-delta
T-cell lymphomas may be a part of a distinct entity of mucocutaneous gamma-delta T-cell lymphomas, the
precise type of T-cell present might be considered to be of greater importance in the
future.  Epstein-Barr virus may be present depending on where the patients are from or if
they are immunosuppressed.
Cytogenetic studies: Approximately half of ETCL are reported to have characteristic chromosome 9q
gains with amplification of 9q34.
The primary target of this amplification may be
the NOTCH1 gene.  Loss of heterozygosity at 9p21 is also reported particularly in cases with
a large cell morphology.  There may be other characteristic chromosomal abnormalities as
well and differences between the monomorphic and other cases.  The 2008 WHO monograph note
the frequent presence of +9q31.3 or -16q12.1 in both types of EATL, +1q32.3-q41 and +5q34-q35.2 more
frequently in the type I versus type II cases and +8q24 (MYC amplifications) more frequently in the type
II than the type I cases. 
The stomach in patients with celiac disease: Celiac disease can be associated with non-neoplastic
lymphoid proliferations in the stomach with an increased incidence of lymphocytic gastritis or simply
increased intraepithelial T-cells.
Furthermore, the lymphocytes in lymphocytic
gastritis are reported to demonstrate an aberrant phenotype similar to that seen in the
enteropathy-associated T-cell lymphomas (surface CD3-, CD8-).
 In addition, particularly in
patients with refractory celiac disease, clonal T-cells are reported in gastric biopsies, most of which
will demonstrate lymphocytic gastritis.  This, together with the report of clonal T-cells in
the peripheral blood of 44% of patients with refractory celiac disease, suggests that EATL is a widely
disseminated disorder. As noted above, gastric involvement by EATL rarely occurs, usually in
association with small intestinal disease.
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