Veterinary Clinical Pathology ISSN 0275-6382
EDITORIAL
Lymphoma in veterinary medicine: no longer a one-word
diagnosis
DOI:10.1111/j.1939-165X.2008.00095.x
In this issue of Veterinary Clinical Pathology, we have
4 case reports of lymphoma and 1 case of thymoma
potentially misdiagnosed as lymphoma.1–5 Why are
these single case reports worthy of our attention? As
with many reported cases of lymphoma, immunop-
henotyping was used as part of the diagnostics in all 5
of these cases and all but 1 had clonality studies per-
formed. However, each offers a twist from the usual,
illustrates the essential diagnostic value of molecular
techniques, and raises critical questions regarding
terminology and tumor classification.
Kelton et al1 describe a horse diagnosed at
postmortem with high-grade, multicentric T-cell lymph-
oma, with T-cell lineage demonstrated by immunohisto-
chemical assessment of CD3. Their description is unique
as the first report of bone marrow necrosis secondary to
lymphoma infiltration in a horse. At postmortem, neo-
plastic cells were found to have diffusely infiltrated mul-
tiple visceral organs, internal lymph nodes, and marrow.
Reading this, our clinician colleagues are likely to ask us:
‘‘With almost complete effacement of marrow, does the
patient have T-cell acute lymphoblastic leukemia (ALL)
or stage V lymphoblastic lymphoma (LBL)?’’ In people,
organomegaly, lymphadenopathy, or a mediastinal mass
plus marrow having o 25% lymphoblasts are criteria
used in the past to distinguish LBL from ALL; however,
what about the patient with both organomegaly and
100% lymphoblasts in the marrow? This issue has been
resolved by the current World Health Organization
(WHO) guidelines, which consolidate ALL and LBL into
a single diagnosis, ie, as 2 manifestations of the same dis-
ease.6 This leads to a second question: ‘‘Based on the ag-
gressive course and morphologic traits of the neoplastic
cells in this horse, can we then amend the diagnosis to ‘T-
cell ALL/LBL’?’’ The answer is no, because the immuno-
phenotypic analysis performed for this patient was lim-
ited to CD3 and CD79a. The designation ALL/LBL applies
only to neoplasia of precursor cells, meaning the anti-
genic array is at the earliest stage of differentiation.6
Precursor T-cell ALL/LBL should be characterized by
testing for an array of T-cell antigens to see if there is
mimicry of the antigens expressed by precursor cells,
360 Vet Clin Pathol 37/4 (2008) 360–362
eg, coexpression of cytoplasmic CD3, CD4, and CD8,
differentiating this neoplasm from peripheral (ie, ‘‘ma-
ture,’’ ‘‘not precursor,’’ or ‘‘postprecursor’’) T-cell and NK-
cell neoplasms. Cells may or may not be positive for
CD34 and surface CD3. Precursor B-cell ALL/LBL cells
coexpress CD19 and CD34 and may or may not express
CD20. CD79a is found at all stages of B-cell development,
so its presence is irrelevant as a means of distinguishing
precursor B-cells from peripheral B-cells. Superimpose
the variety of aberrant antigenic expressions on this
overly simplified construct describing precursor cell
immunophenotypes, and the difficulty in identifying a
precursor cell tumor becomes staggering.7,8 Further-
more, given that morphology does not necessarily iden-
tify a cell as a lymphoblast (a term narrowly applied in
human hematopathology to describe precursor B and T
cells), the diagnosis of ALL/LBL hinges more on
immunophenotype than morphology, as small lymph-
ocytes can have a precursor immunophenotype.
Kodama et al2 report on a case of a dog diagnosed
with B-cell extranodal (intestinal) lymphoma. This
case falls within the broad category of a peripheral
(postprecursor) B-cell lymphoma. It manifested 2 mor-
phologic subsets—neoplastic cells with either lymph-
oid or Mott cell features—but both subsets were deter-
mined by immunohistochemical and clonality studies
to be a single population of cells of B-cell lineage. The
coexistence of lymphoid and Mott cell morphologies
within this intestinal lymphoma is a first, and this di-
agnosis would not have been possible without the ev-
idence provided by immunophenotyping and PCR for
antigen receptor rearrangements (PARR). Does this
case fit the WHO definition of a lymphoplasmacytic
lymphoma (LPL)? No, it does not. In a cytologic prep-
aration, LPL more closely mimics a reactive lymph
node, consisting of small lymphocytes, plasmacytoid
lymphocytes, and plasma cells.9 Furthermore, LPL has
an indolent course, is not generally extranodal, and
has a low mitotic index. The pattern detected in this
patient does not fit current WHO classifications so it
may be unique to dogs and perhaps unique to Dachs-
hunds. Can we apply the term ‘‘biphenotypic’’ to this
c 2008 American Society for Veterinary Clinical Pathology
EDITORIAL
lymphoma? Again, the answer is no. The term ‘‘biphe-
notypic’’ is generally applied to the rare acute leukemia
that coexpresses lymphoid (B- or T-cell) and myeloid
markers, or both B- and T-cell markers.10
Flatland et al3 describe a cat with extranodal (spi-
nal) anaplastic B-cell lymphoma with uniquely large,
vacuolated histiocytoid cells, more aligned with a
histiocytic neoplasm. The tumor was determined by
immunophenotyping to be lymphoma. Although
clonality is assumed to exist in a neoplastic prolifera-
tion, clonality could not be confirmed in this cat’s tu-
mor. The authors cite a previous study demonstrating
that PARR has low sensitivity for feline B-cell lympho-
mas, with only 52.5% positive results.11 CD79a stain-
ing, although potentially supportive of the B-cell
lineage, resulted in nonspecific nuclear staining and
could not be interpreted as definitively positive, a com-
plication important to consider before diagnosing ab-
errant coexpression of CD3 and CD79a, which would
be suspicious for a biphenotypic lymphoma.
Carter et al4 report on a cat with low-grade
erythrophagocytic hepatosplenic T-cell lymphoma. Pe-
ripheral T-cell lymphoma has been described previ-
ously in cats, but the tissue distribution of neoplastic
cells in this cat was similar to that of hepatosplenic
T-cell lymphoma in people and dogs, with preferential
localization in hepatic and splenic sinusoids.12 Unlike
the human and canine cases, this patient’s disease had
an indolent course, suggesting a low-grade variant. As
with the above cases, the diagnosis depended on
immunophenotypic analysis and clonality studies.
Finally, this case series includes 1 tumor that was
not lymphoma, but could have been confused with
one. The significant unique feature of this case, as re-
ported by Lara-Garcia et al,5 was the ectopic location of
a lymphocyte-predominant thymoma in a cervical site.
The early differential diagnosis included precursor
T-cell lymphoma (cells were CD31, CD41, and CD81),
Hodgkin-like lymphoma, and T-cell-rich B-cell lym-
phoma. PARR for both T- and B-cell antigen receptor
genes was negative. Cytokeratin-positive cells detected
after surgical removal of the tumor confirmed the mass
as a thymoma.
In summary, the 5 cases in this issue of Veterinary
Clinical Pathology demonstrate successful use of
immunophenotyping and ancillary tests to diagnose
(and rule out) lymphoma. They offer interest as stand-
alone papers, but together they indicate a need for ex-
pansion of test availability at the reference laboratory
level (as well as comprehensive resident training in
hematopathology13,14) to allow more precise diag-
noses of lymphoma in animal patients and more care-
ful application of lymphoma nomenclature and
Vet Clin Pathol 37/4 (2008) 360–362
c 2008 American Society for Veterinary Clinical Pathology
classification schemes. Just as our counterparts in
medical hematopathology have determined that there
are more than 30 types of lymphoma, we, too, are
finding that the one-word diagnosis of ‘‘lymphoma’’
cannot persist, as evidenced by recent efforts at classi-
fication of lymphomas in animals15 and by these 5
examples. Greater depth in understanding the types of
lymphoma we see in the diagnostic laboratory and a
more careful application of language and classification
systems will facilitate an exchange of information be-
tween the medical and veterinary medical worlds,
which can only be a benefit to both our patient groups.
Patricia McManus
Section Editor
Hematology and Immunology
IDEXX Reference Laboratories
patricia-mcmanus@idexx.com
References
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2. Kodama A, Sakai H, Kobayashi K, et al. B-cell intestinal
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EDITORIAL
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c 2008 American Society for Veterinary Clinical Pathology