Hematopathology Diagnoses Too Easy to Miss!
Malignant Lymphomas Mimicking Reactive Processes (continued)
Marsha Kinney, James Cook and Steven Swerdlow
Extranodal NK/T-cell lymphoma, nasal type
39 year old male with pre-op diagnosis of "chronic
laryngitis". Biopsy is of right subglottic area. After the case was signed out, additional history,
which was actually known at our institution, was obtained by the original pathologist. About two years
earlier the patient had right and left turbinate biopsies which demonstrated an extranodal NK/T-cell
lymphoma, nasal type. The patient was treated following his recurrence. As of about 2 years later
(8/06), he has a mildly positive PET scan in his turbinate that is of uncertain significance. The
remainder of his scan was negative. No further follow-up.
The small biopsies demonstrated an ulcerated dense
diffuse somewhat polymorphous infiltrate. The ulcerated area showed neutrophils admixed with some
lymphoid cells and plasma cells. Elsewhere there were numerous mostly small to intermediate-sized
lymphoid cells, often with irregular nuclear contours admixed with somewhat variable numbers of plasma
cells. The cells showed infiltration into the overlying epithelium. A Grocott stain was negative.
Flow cytometric immunophenotypic studies:
Paraffin section immunohistochemistry/in situ hybridization (ISH) :
- CD20 – Few scattered positive cells.
- CD3 – Moderate number of scattered positive strongly staining
cells, numerous positive weakly staining cells.
- CD5 – Moderate number of scattered positive cells, probably
similar to pattern of strongly staining CD3 positive cells (ie, many CD3+ cells are negative).
- CD4 – Moderate number of scattered strongly positive cells,
plus staining of histiocytes, many lymphocytes are negative.
- CD8 – Few scattered positive cells.
- CD56 – Numerous positive cells in some areas.
- Granzyme B – Many positive cells.
- EBER ISH for EBV – Many positive cells.
Genotypic & Cytogenetic studies:
This biopsy, submitted with a pre-operative diagnosis
of chronic laryngitis, was originally diagnosed as demonstrating a "dense lymphoid infiltrate associated
with acute inflammation, ulcer and atypia of squamous mucosa, most consistent with reactive atypia."
After the case was signed out, the surgeon called and informed the pathologist that the patient had a
previous biopsy of lymphoma. At this point the pathologist became concerned and sent the case for
consultation with the question "Does this represent recurrence of the patient's lymphoma?" The
histopathology was reviewed as was the patient's prior biopsy which had been seen at our institution and
diagnosed as an extranodal NK/T cell lymphoma, nasal type. The diagnosis was then confirmed using
paraffin section immunohistochemistry and an in situ hybridization stain for Epstein-Barr virus.
This case illustrates the following:
- Knowing a patient's clinical history can turn a potentially
difficult case into one that is much easier to diagnose.
- Although in this case the location, particularly of the
original biopsy suggested the diagnosis, remember that not all extranodal NK/T cell lymphomas of nasal
type occur in the nose and, not all nasal lymphomas are NK/ T cell in origin.
- Extranodal and NK/T cell lymphomas of nasal type can be
confused with inflammatory infiltrates due to the presence of admixed acute inflammatory cells in areas
of ulceration or necrosis and admixed chronic inflammatory cells.
- The histopathologic features that should raise strong suspicion
for a lymphoid neoplasm in this case include the dense infiltrate and at least somewhat enlarged lymphoid
cells oftentimes with irregular nuclear contours.
- Biopsies of extranodal NK/T cell lymphomas of nasal type may
not always demonstrate angiocentricity or areas of significant necrosis.
- Immunohistochemical stains and in situ hybridization for the
Epstein-Barr virus are critical in confirming the diagnosis in a case such as this. Selection of
appropriate stains requires knowing something about the differential diagnosis for lymphomas with this
histopathologic appearance and at this site.
- One should not be shy about doing at least limited
immunohistochemical stains as a quality assurance tool for yourself in evaluating lymphoid proliferations
that raise any question of a malignant lymphoma.
- Standard genotypic studies looking for evidence of a B-cell or
T cell clone would not be helpful in confirming the neoplastic nature of this infiltrate since this type
of lymphoma is usually of natural killer cell origin.
Extranodal T/NK Cell Lymphomas:
One of the major differences between the WHO lymphoma classification
and many of those that preceded it is the specific identification of a significant number of distinctive
extranodal lymphomas. Although not very common (at least in the U.S.), a major set of these are the
extranodal T/NK lymphomas which include enteropathy-type T-cell lymphoma (ETCL), subcutaneous
panniculitis-like T-cell lymphoma (SCPTCL), extranodal NK/T-cell lymphoma, nasal type and hepatosplenic
All of these lymphomas share many features including the fact that their
diagnosis requires a combination of morphologic, immunophenotypic and anatomic information. All can have
a variable cytologic appearance and all are composed of cytotoxic T or NK cells as identified by
expression of the cytotoxic T cell associated granule TIA-1 with or without other cytotoxic T-cell
associated proteins (granzyme, perforin). Even within one entity there can be major phenotypic
differences, which, at least at this point in time, are generally not considered to be important. One
exception to this is that, as currently defined, SCPTCL must be of alpha-beta T-cell type. Lymph node
involvement is infrequent in many of these lymphomas and, except for the newly defined SCPTCL, they are
considered to be very aggressive neoplasms.
Extranodal NK/T-cell lymphoma, nasal type
Making the diagnosis:
The diagnosis of extranodal NK/T
cell lymphoma, nasal type is made based on the anatomic site of the lymphoma (but remember not all occur
in the nose and not all nasal lymphomas are NK/T cell lymphomas), the histopathology (which is not very
specific) and immunophenotypic and other ancillary studies.
Histologic sections demonstrate a diffuse proliferation of
small, medium, large and/or anaplastic "atypical" lymphoid cells.
The neoplastic cells
will have azurophilic granules on touch imprints stained with Romanovsky-type stains. Necrosis is very
common but angiocentricity is reported in less than half to two thirds of cases. The necrosis present is
believed to be due at least in part to factors such as chemokines or cytokines.
A lack of
angiodestruction and necrosis is reported to be associated with cases of "small cell type". 
There may be many admixed acute and chronic inflammatory cells. These morphologic findings will lead to
a differential diagnosis that, among other things, includes benign inflammatory processes and nasal
lymphomas not of NK/T-cell type including other angiocentric lymphomas. Conversely, reactive
proliferations can be confused with NK/T cell lymphomas. 
Most cases have the phenotype of true natural
killer cells (but some are T-cell neoplasms).
They demonstrate the following phenotype:
surface CD3-, cytoplasmic CD3ε+, CD2+, CD5-, CD7± and most cases are CD4 and CD8 negative.
Cytotoxic markers, such as TIA1 or granzyme B, are positive as is the NK-cell associated marker CD56.
CD16 and CD57 are not expressed. Cases are almost invariably EBV positive as identified using EBER-1
in-situ hybridization. CD30 expression may be present.9
It should be remembered that, as with other lymphomas, not all cases have a typical phenotype. For
example, in the study from the Massachusetts General Hospital, some cases were CD3 negative, one even
CD45 negative and they documented CD56 expression in only half of the cases studied.  Others
also find atypical phenotypes, such as cases with a lack of CD56 expression in paraffin sections.
Rare cases lacking at least one of the cytotoxic markers have been reported, and some report
EBV negative cases.
The 2008 WHO chapter specifically requires that cytotoxic molecules
and EBV present to make the diagnosis in a CD3e+ CD56- case.  CD3+, CD56-, EBV-, cytotoxic
molecules negative cases are to be diagnosed as peripheral T-cell lymphoma, not otherwise specified.
EBV- cases "should be accepted with some skepticism". 
Extranodal NK/T-cell lymphomas of
nasal type most typically occur as localized destructive nasal lesion. They may, however, involve other
parts of the upper aerodigestive tract or sometimes other sites (hence the term "nasal type"). They are
most common in the Orient but occur in the West. Their median survival is described as poor in the
Orient (12.5 months in nasal/nasopharyngeal NK/T cell lymphomas in one series
; however, a
study from the Massachusetts General Hospital reported an outcome similar to sinonasal diffuse large
B-cell lymphomas.  Nasal NK/T lymphomas can be associated with a hemophagocytic (macrophage
activation) syndrome, which is an important cause of mortality in these patients. They can also involve
lymph nodes and disseminate widely to other extranodal sites. Extra-upper aerodigestive tract cases are
reported to have a worse prognosis.  These authors suggest that this is a better way of
recognizing a more aggressive group of cases rather than dividing cases into nasal versus extra-nasal
locations. The International Prognostic Index is also prognostically useful in these cases as is "local
In most studies, cell size is not of independent prognostic
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