Extranodal NK/T-cell Lymphoma, Nasal Type

 
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Extranodal NK/T-cell Lymphoma, Nasal Type
ORIGINAL ARTICLE

                Extranodal NK/T-cell Lymphoma, Nasal Type
                  A Report of 73 Cases at MD Anderson Cancer Center
   Shaoying Li, MD,* Xiaoli Feng, MD,* Ting Li, MD,w Shuang Zhang, MD,w Zhuang Zuo, MD, PhD,*
          Pei Lin, MD,* Sergej Konoplev, MD, PhD,* Carlos E. Bueso-Ramos, MD, PhD,*
      Francisco Vega, MD, PhD,* L. Jeffrey Medeiros, MD,* and C. Cameron Yin, MD, PhD*

Abstract: Extranodal NK/T-cell lymphoma, nasal type
(ENKTL) is uncommon in the United States. We report 73
                                                                           E   xtranodal NK/T-cell lymphoma, nasal type (ENKTL)
                                                                               is a rare type of lymphoma that is endemic to East
                                                                           Asia and parts of Central and South America. Most (80%
patients with ENKTL, including 49 men and 24 women (median                 to 90%) patients present with nasal obstruction, sinusitis,
age, 46 y). Sixty-three patients had nasal/upper aerodigestive             ulcer, and epistaxis due to a destructive mass involving
tract disease; 10 had extranasal disease involving skin, small             the midline facial tissues. ENKTL most often presents as
intestine, epiglottis, testis, adrenal glands, kidney, and breast.         a localized disease, clinical stage I-II; however, wide-
Complete staging data were available for 68 patients: 44 stage             spread dissemination can occur in a subset of patients.
I/II and 24 stage IV. Fifteen of 69 (22%) had lymphadenopathy              Occasionally, patients with ENKTL present with only
and 10/63 had bone marrow involvement. Histologically, 67/73               extranasal sites of disease, most often skin, lung, and
(92%) showed necrosis, and 48/70 (69%) had an angiocentric/                gastrointestinal tract, but a variety of other extranasal
angiodestructive growth pattern. The neoplastic cells showed a             sites have been reported.1–9
wide spectrum: medium sized (n = 34), mixed small and large                       Accurate diagnosis of ENKTL can be challenging,
(n = 21), large (n = 13), and small (n = 5). In situ hybridization         especially in small biopsy specimens or in frozen sections,
for Epstein-Barr virus–encoded small RNA was positive in every             as the neoplastic cells are often admixed with in-
case. Immunohistochemical studies showed expression of cyto-               flammatory cells and necrosis. An angiocentric and an-
toxic markers (100%), T-bet (96%), CD2 (96%), CD3 (93%),                   giodestructive growth pattern is common and has been
CD56 (90%), and ETS-1 (64%). Ki-67 was Z60% in 46%                         emphasized in the literature, but this pattern is not in-
cases. Therapy was known for 64 patients; 14 received only                 variable.1 Most cases of ENKTL are thought to be of
chemotherapy, 8 radiation alone, and 42 received combined                  NK-cell lineage or derived from an NK/T-cell precursor
radiation and chemotherapy. Median survival was 4.2 years,                 cell, but a subset of cases meets the criteria for T-cell
and 5-year overall survival was 46% (median follow-up, 3.8 y).             lineage.1 In the 2008 World Health Organization classi-
Extranasal disease, high International Prognostic Index score,             fication, presence of Epstein-Barr virus (EBV), usually
and high proliferation rate correlated with poorer prognosis. We           shown by assessment for EBV-encoded small RNA
conclude that ENKTL cases in the United States are similar to              (EBER), was included in the disease definition, and EBV
those reported in Asia and other countries. Absence of the an-             has been implicated in disease pathogenesis.1,10–13
giocentric/angiodestructive pattern and presence of lympha-                       Although the clinicopathologic features of ENKTL
denopathy, features underemphasized in the literature, occurred            are well recognized, most current data are derived from
in appreciable subsets of patients. The International Prognostic           patient populations in endemic regions, particularly East
Index score, anatomic site of disease, and proliferation rate had          Asia.3,5–7 Data on patients with ENKTL in developed
prognostic value in this patient cohort.                                   countries are limited.9 In this study, we report the clin-
Key Words: extranodal NK/T-cell lymphoma, nasal type,                      icopathologic and immunophenotypic features of a large
southern United States                                                     series of patients with ENKTL at our institution in the
                                                                           United States.
(Am J Surg Pathol 2013;37:14–23)

                                                                                       MATERIALS AND METHODS
From the *Department of Hematopathology, The University of Texas           Case Selection
   MD Anderson Cancer Center, Houston, TX; and wDepartment of
   Pathology, Peking University First Hospital, Beijing, China.                  We searched the database of the Department of
Conflicts of Interest and Source of Funding: The authors have disclosed     Hematopathology at The University of Texas MD An-
   that they have no significant relationships with, or financial interest   derson Cancer Center from January 1, 1985 to March 31,
   in, any commercial companies pertaining to this article.                2012 for cases of ENKTL. The diagnosis was based on
Correspondence: C. Cameron Yin, MD, PhD, Department of Hema-
   topathology, The University of Texas MD Anderson Cancer Center,         morphologic and immunophenotypic criteria as specified
   Houston, TX 77030 (e-mail: cyin@mdanderson.org).                        in the World Health Organization classification.1 Clinical
Copyright r 2012 by Lippincott Williams & Wilkins                          information was obtained by review of medical records.

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Extranodal NK/T-cell Lymphoma, Nasal Type
Am J Surg Pathol      Volume 37, Number 1, January 2013                                Nasal ENKTL From the United States

Hematoxylin-eosin-stained slides of tissue biopsy and                                  RESULTS
bone marrow biopsy specimens and Wright-Giemsa-
stained bone marrow aspirate smears and touch imprints         Clinical Features
were reviewed.                                                       The study group was composed of 73 patients with
                                                               ENKTL, including 49 men and 24 women. The median
                                                               age at the time of diagnosis was 46 years (range, 18 to
Immunophenotypic Analysis                                      88 y). There were 43 (59%) whites, 18 (25%) Hispanics, 8
      Immunohistochemical studies were performed using         (11%) Asians, 2 (3%) African Americans, and 2 patients
formalin-fixed, paraffin-embedded tissue sections as de-          of unknown race. Sixteen of 67 (24%) patients with
scribed previously.14 Tissue sections of 4 mm thickness        available history had B-type symptoms. Sixty-three (86%)
were deparaffinized, and endogenous peroxidase was               patients had tumors in the nasal/upper aerodigestive tract
blocked with hydrogen peroxide. Heat-induced epitope           region, and 10 presented with extranasal sites of in-
retrieval was performed using citrate buffer, pH 6.0. The       volvement. Patients with nasal disease presented with
monoclonal antibodies used are specific for CD2, CD3,           nonspecific sinonasal symptoms, such as nasal ob-
CD4, CD5, CD7, CD8, CD20, CD30, CD56, TIA-1,                   struction, nasal drainage, or facial swelling. Forty-four
granzyme B, Ki-67 (Dako, Carpinteria, CA), CXCL13              (60%) patients had localized disease, stage I or II, and 24
(R&D Systems, Minneapolis, MN), and PD-1 (Cell                 patients had stage IV disease; complete staging in-
Marque, Rocklin, CA). Analysis for T-bet (H-210; 1:100;        formation was not available for 5 patients. Ten patients
Santa Cruz, Santa Cruz, CA) and ETS-1 (1G11, 1:100;            presented with extranasal disease involving the following
Santa Cruz) was performed using N-Histofine detection           sites: skin (n = 3), small intestine (n = 2), epiglottis
kit (Nichirei Biosciences Inc., Japan). Nuclear staining for   (n = 1), testis (n = 1), bilateral adrenal glands (n = 1),
T-bet and ETS-1 was considered positive as reported            kidney (n = 1), and breast (n = 1). Seven of 10 patients
previously.15 In situ hybridization analysis for EBER was      with extranasal disease had complete staging information:
performed for all cases as described previously.14             stage IV (n = 4), stage II (n = 1), and stage I (n = 2).
      Flow cytometry immunophenotypic analysis was             Twenty-four (33%) patients had >1 site involved. Fifteen
performed on cell suspensions of tissue biopsy or bone         of 69 (22%) patients with complete clinical data had
marrow aspirate specimens using a FACScan or FACS-             lymphadenopathy, and most of these patients had nasal
Calibur instrument (Becton-Dickinson Biosciences, San          disease. Ten of 63 (16%) patients assessed had bone
Jose, CA) as described previously.16 The lymphocyte            marrow involvement.
population was gated using side scatter and CD45 ex-                 Laboratory data were available for 66 patients. Ten
pression. The panel of monoclonal antibodies included          (15%) patients had a hemoglobin level of
Extranodal NK/T-cell Lymphoma, Nasal Type
Li et al                                                                       Am J Surg Pathol      Volume 37, Number 1, January 2013

                                                                         the third case the neoplastic cells were a mixture of small
TABLE 1. Clinical Features of ENKTL
                                                                         and large cells. Two patients presented with gastro-
Features                      Presence         Total       Presence%     intestinal disease involving the ileum or jejunum. The
Age >60 y                        14             73              19       patients with disease in the ileum underwent segmental
Male                             49             73              67       resection of the ileum revealing a 4.5  4.5  4.0 cm mass
White                            43             73              59
Extranasal                       10             73              14
                                                                         associated with a perforation (Fig. 2). Microscopic ex-
Nasal                            63             73              86       amination of both tumors in the gastrointestinal tract
B-symptoms                       16             67              24       revealed that they were composed of small to medium-
Smoking                          34             68              50       sized cells associated with necrosis, mucosal ulcer, and an
Hb < 11 g/dL                     10             66              15       angiocentric growth pattern (Fig. 2). One patient had a
Platelet  2                          17             63              27       periadrenal fat were diffusely replaced by a monomorphic
Ki-67Z60%                        18             39              46       population of medium-sized lymphoid cells with brisk
Large cell morphology            13             71              18       mitotic activity (Fig. 3C). The clinical features of this case
   BM indicates bone marrow; Hb, hemoglobin.                             have been reported previously.18 In 1 patient, a core
                                                                         needle biopsy specimen from the right kidney and peri-
                                                                         renal adipose tissue were effaced by ENKTL composed of
                                                                         a diffuse proliferation of large lymphoma cells with ir-
Cytologically, the lymphoma cells exhibited a broad                      regular nuclei, distinct nucleoli, and dispersed chromatin.
spectrum, ranging from small (n = 5, 7%), to medium                      One case involved the epiglottis and was composed of
sized (n = 34, 46%), to large (n = 13, 18%), or mixed                    medium-sized cells with an angiocentric pattern, an-
small and large cells (n = 21, 29%) Fig. 1). In 1 neoplasm               gioinvasion, and necrosis. In the patient who had
composed of large cells the neoplastic cells had anaplastic              ENKTL involving the breast, the neoplasm was asso-
features.                                                                ciated with a breast implant placed for cosmetic reasons.
      The 10 extranasal cases are described here in more                 This neoplasm was a diffuse proliferation composed of
detail. Skin biopsy specimens in 3 patients showed an                    medium-sized and large neoplastic cells extensively in-
extensive perivascular infiltrate within the dermis and                   volving breast parenchyma associated with extensive co-
subcutis. In 1 case, the infiltrate was composed of large                 agulative necrosis, numerous mitotic figures, and
lymphoid cells with irregular nuclei, fine chromatin, and                 apoptotic cells (Fig. 3D). Angiocentricity with angioin-
inconspicuous nucleoli. In a second case, the infiltrate was              vasion was identified, but these areas were not a major
composed predominantly of medium-sized cells, and in                     component of the tumor.

TABLE 2. Clinical Features of ENKTL: Extranasal Group Versus Nasal Group
                                                       Extranasal                                                  Nasal
Features                          Presence              Total          Presence%            Presence               Total          Presence%
Age >60 y                              1                 10               10                  13                    63                21
Male                                   7                 10               70                  42                    63                67
White                                  5                 10               50                  38                    63                60
B-symptoms                             4                  7               57                  12                    60                20
Smoking                                3                  7               43                  31                    61                51
Hb < 11 g/dL                           2                  7               29                   8                    59                14
Platelet  2                                2                  6               33                  15                    57                26
Ki-67Z60%                              3                  4               75                  15                    39                38
Large cell morphology                  3                 10               30                  10                    61                16
   BM indicates bone marrow; Hb, hemoglobin.

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Extranodal NK/T-cell Lymphoma, Nasal Type
Am J Surg Pathol      Volume 37, Number 1, January 2013                                    Nasal ENKTL From the United States

FIGURE 1. Microscopic features of ENKTL. The neoplastic cells exhibited a broad spectrum, ranging from small (A), to medium
sized (B), to large cells (C) (hematoxylin and eosin).

Immunophenotypic and Molecular Results                            CD5, and B-cell antigens. CD56 was positive in all 8 cases
     Flow cytometry immunophenotypic analysis was                 assessed.
performed on 11 cases. In every case the neoplastic cells               Immunohistochemical analysis was performed on
were positive for CD2, but negative for surface CD3,              most cases. The antibody panel used was variable over

FIGURE 2. Morphologic features of a case of ENKTL in ileum. A, Grossly, the tumor presents as a fungating mass associated with a
perforation. B, Low-power view shows that the tumor is associated with necrosis and mucosal ulcer (hematoxylin and eosin). C,
High-power view shows that the tumor is composed of small to medium-sized cells with an angiocentric growth pattern
(hematoxylin and eosin). D, The lymphoma cells are positive for EBER by in situ hybridization.

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Li et al                                                                Am J Surg Pathol             Volume 37, Number 1, January 2013

FIGURE 3. Microscopic features of 3 cases of ENKTL arising from extranasal sites. A and B, A case of ENKTL arising from testis. The
tumor is composed of large neoplastic cells associated with mitotic figures and necrosis (hematoxylin and eosin). C, A case of
ENKTL arising from the adrenal gland. The adrenal parenchyma and periadrenal fat were replaced by a monomorphic population
of medium-sized cells (hematoxylin and eosin). D, A case of ENKTL involving the breast. The tumor cells are medium-sized to
large and are associated with angioinvasion, necrosis, and mitotic figures (hematoxylin and eosin).

time. For this study, additional immunostaining analyses           cases, we assessed for CXCL13 and PD-1 expression. For
were performed on cases with available unstained slides.           each antibody 4 cases (40%) were positive, but these
The neoplastic cells expressed CD2 (22/23; 96%), CD3               antigens were not expressed by the same 4 cases. In situ
(68/73; 93%), CD4 (9/31; 29%), CD5 (7/39; 18%), CD7                hybridization analysis for EBER was positive in all 73
(10/25; 40%), CD8 (11/33; 33%), CD30 (17/40; 43%),                 cases and in virtually all cells of each case (Fig. 4).
and CD56 (62/69; 90%). For the 7 cases negative for                      T-cell receptor-g gene rearrangement analysis was
CD56 by immunohistochemical analysis, 4 were assessed              performed on 20 cases, including 15 nasal and 5 extra-
by flow cytometry, and all were positive for CD56. All              nasal tumors. Monoclonal T-cell receptor-g gene
cases assessed expressed cytotoxic granule-associated
proteins, either TIA-1 (n = 30) or granzyme B (n = 19) or
both (n = 17). T-bet and ETS-1 were positive in 24/25              TABLE 3. Expression of T-bet and ETS-1 in Cases of ENKTL
(96%) and 16/25 (64%) of the cases, respectively                                T-bet (n = 25), [N (%)]              ETS-1 (n = 25), [N (%)]
(Table 3). The proliferation index, as demonstrated by the
                                                                                           1   (4)                            9   (36)
MIB1 (Ki-67) antibody, was assessed in 39 cases and                1+                      3   (12)                           1   (4)
showed a median proliferation rate of 50% (range, 5% to            2+                      6   (24)                           7   (28)
95%). Fifteen cases showed a low (< 30%) proliferation             3+                     15   (60)                           8   (32)
rate, 6 had medium (30% to 59%) proliferative activity,                  indicates negative.
and 18 showed high (Z60%) proliferative activity. In 10

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Am J Surg Pathol      Volume 37, Number 1, January 2013                                 Nasal ENKTL From the United States

FIGURE 4. Immunohistochemical findings of ENKTL. Immunostains show that the tumor cells are positive for CD3 (A), CD56 (B),
and TIA-1 (C). The lymphoma cells are positive for EBER by in situ hybridization (D).

rearrangements were identified in 8 (40%) cases, including      vincristine, and prednisone. Fourteen patients received
4 (27%) nasal and 4 (80%) extranasal cases. The                stem cell transplantation. Treatment information was not
frequency of T-cell receptor gene rearrangements in nasal      available for 9 patients.
versus extranasal tumors was not statistically significant            For the 44 patients with low-stage (stage I/II) dis-
(P = 0.10; Fisher exact test).                                 ease, 7 were treated with radiation alone, 2 chemotherapy
      On the basis of combined immunophenotypic data           alone, and 30 received combined radiation and chemo-
and molecular results we were able to determine the lin-       therapy. For 5 patients, no treatment information is
eage of the neoplasms in 41 cases. Twenty-four of 41           available. OS was significantly better for patients treated
(59%) ENKTL were of NK-cell lineage, and 17 (41%)              with combined radiation and chemotherapy rather than
cases were of T-cell lineage. In the subgroup of 11 cases      radiation therapy alone (8.33 vs. 1.51 y, P = 0.013). For
assessed by flow cytometry and shown to be negative for         the 24 patients with stage IV disease, there was no sig-
surface CD3, 2 cases had monoclonal T-cell receptor-g          nificant difference in OS between patients treated with
gene rearrangements and were therefore classified as            combined radiation and chemotherapy versus chemo-
T-cell lineage. In 32 cases in this study the data were        therapy alone (P = 0.29; Fig. 5).
incomplete, and lineage could not be assigned.                       With a median follow-up of 3.8 years (range, 0.04 to
                                                               19.33 y), 30 (42%) patients died. The median OS was
Treatment and Clinical Outcome                                 4.2 years (95% confidence interval, 1.27-7.07 y), and
      Fourteen patients were treated with various che-         the 5-year OS was 46%. The median PFS was 3 years
motherapy regimens, 8 patients were treated only with          (95% confidence interval, 2.17-4.29 y). Patients with ex-
radiation therapy, and 42 received combined radiation          tranasal disease had a significant shorter OS compared
and chemotherapy. The most commonly used chemo-                with patients who had nasal disease (0.55 vs. 5.01 y;
therapy regimen was cyclophosphamide, doxorubicin,             P = 0.045).

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Li et al                                                                                 Am J Surg Pathol      Volume 37, Number 1, January 2013

FIGURE 5. Overall survival of patients with ENKTL by therapy. A, Stage I/II. B, Stage IV.

Prognostic Factors                                                              (Fig. 6). After adjusting for therapy, extranasal disease
      We performed univariate analysis to evaluate the                          (P = 0.005, hazard ratio = 69.04) and IPI score >2
association between 17 clinicopathologic features and                           (P = 0.037, hazard ratio = 29.58) were independent risk
prognosis (Table 4). The results showed that extranasal                         factors for worse OS (P = 0.005). Among the 17 factors
disease, hemoglobin  2 were associated with poorer OS
(P < 0.05). Except for extranasal disease, ALC < 1000/
mL, elevated serum LDH, and large cell morphology,                                                          DISCUSSION
these factors were also associated with a worse PFS                                   ENKTL has a strong ethnic and geographic predi-
(P < 0.05). Presence of B-symptoms and thrombocyto-                             lection, being most common in Asia and in Native
penia (platelet  60 vs. r60 y)                      0.275             1.90             0.64-5.58                  0.486              1.43           0.52-3.90
Sex                                       0.490             1.25             0.57-2.74                  0.660              1.19           0.54-2.63
B-symptoms                                0.064             2.36             0.95-5.87                  0.047              2.54           1.00-6.44
Smoking                                   0.352             1.45             0.67-3.14                  0.171              1.73           0.79-3.77
Hb (< 11 vs. Z11 g/dL)                    0.037             3.83             1.09-12.55                 0.035              3.94           1.10-13.99
Platelet (low vs. normal)                 0.060             2.74             0.92-8.19                  0.001              9.87           2.51-38.79
ALC (< 1000 vs. Z1000/mL)                 0.023             2.52             1.14-5.59                  0.078              2.08           0.96-4.54
LDH (high vs. normal)                     0.011             3.10             1.30-7.34                  0.063              2.16           0.96-4.91
b2M (high vs. normal)                     0.027             3.53             1.15-10.67                 0.033              3.37           1.12-10.65
Lymphadenopathy                           0.230             0.60             0.26-1.38                  0.280              0.63           0.27-1.46
BM involvement                            0.311             1.98             0.54-7.97                  0.375              1.79           0.49-6.52
Extranodal sites Z2                       0.008             3.27             1.37-7.82                  0.001              4.63           1.83-11.72
Ki-67 (Z60% vs.  2 vs. r2)                          0.000            10.50             3.67-32.47                 0.001              6.87           2.38-18.16
   BM indicates bone marrow; CI, confidence interval; Hb, hemoglobin; HR, hazard ratio.

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Am J Surg Pathol      Volume 37, Number 1, January 2013                                   Nasal ENKTL From the United States

FIGURE 6. Survival of patients with ENKTL by IPI. A, OS. B, PFS.

series from Asian countries,3,5–7 with a recent large study        shown). None of these B-cell lymphomas was positive for
from Brazil2 and only rare reports of small series from            T-bet or ETS-1. These results suggest that T-bet and ETS-
developed countries.9 In this study, we analyzed the               1 may have biological roles in ENKTL pathogenesis. The
clinicopathologic, immunophenotypic, and prognostic                results also indicate that T-bet is a sensitive marker for
characteristics of 73 cases of ENKTL seen at our in-               ENKTL, equivalent to pan-T/NK markers such as CD2
stitution in the United States. The clinical features of this      or CD3 but more specific for ENKTL. Therefore, we
cohort are similar to those reported in Asian countries,5–7        conclude that T-bet can be a valuable addition to an
with a male predominance, a wide age range with a me-              antibody panel for the workup of suspected cases of
dian age at diagnosis of 46 years, a predilection for the          ENKTL.
nasal cavity and paranasal sinuses, and an association                    We also assessed for expression of 2 follicular T-
with nonspecific symptoms related to nasal obstruction              helper–associated markers, CXCL13 and PD-1, in a small
or sinusitis. Unlike other studies, however, in this study         subset of cases and found that each marker was expressed
extranasal disease was relatively less common. The                 in 40% of cases, in an apparently mutually exclusive
ratio of extranasal to nasal disease in this study, 1 to 6.3,      manner. We initially found these results surprising as
was much lower compared with ratios of approxi-                    ENKTL is thought to be derived from cytotoxic NK or T
mately 1 to 3 or 4 in other studies in the literature.3,5,9,19     cells. However, Gualco et al2 showed CXCL13 expression
       Recently, newer markers have been used in the               in a small subset of the ENKTL cases they studied, and
evaluation of ENKTL. We assessed these markers in a                more recently Pongpruttipan et al20 suggested that
subset of cases with available blocks or unstained slides.         CXCL13 was expressed more frequently in ENKTL of
T-bet is a transcription factor that plays an essential role       NK-cell lineage, whereas PD-1 was seen more often in
in the development and differentiation of lymphocytes.              ENKTL of T-cell lineage. We could not appreciate this
T-bet is expressed widely in CD8+ T lymphocytes, NK                correlation, but the number of cases we assessed was too
cells, a subset of B cells, monocytes, and dendritic cells.15      small to draw any conclusions.
T-bet has also been reported to be overexpressed in                       The role of proliferation rate in the prognosis of
ENKTL and a subset of unspecified cases of peripheral T-            patients with ENKTL has been reported in only a few
cell lymphoma but not in most B-cell lymphomas.15 ETS-             studies in the literature. Ki-67Z65% has been reported
1 has been shown to be an important cofactor of T-bet              to be associated with worse prognosis in stage I/II
and positively regulates the development and cytotoxic             ENKTL,21 and Ki-67 > 50% predicted poor OS in an-
function of NK cells.15 ETS-1 has also been reported to            other study.3 Our results showed that Ki-67Z60% pre-
be expressed in ENKTL but not in peripheral T-cell                 dicted poorer OS and PFS. For the 39 cases with Ki-67
lymphoma or B-cell lymphomas.15 To date, most cases of             results available, 18 (46%) had Ki-67Z60%. The OS for
ENKTL assessed for T-bet and ETS-1 have been from                  patients with ENKTL with Ki-67Z60% was 2.68 years
Asia. In this study, we used immunohistochemical                   versus 5.83 years for patients with ENKTL with
methods to assess for T-bet and ETS-1, and these markers           Ki-67 < 60% (P = 0.01). Similarly, PFS was shorter for
were expressed in 96% and 64% of cases, respectively.              patients with ENKTL with high Ki-67: 2.25 years if Ki-
For the sake of comparison, we also assessed 10 B-cell             67Z60% versus 4.17 years if Ki-67 < 60% (P = 0.03).
lymphomas for T-bet or ETS-1 expression, including                        The median survival and 5-year OS of patients with
diffuse large B-cell lymphoma (n = 5), follicular lym-              ENKTL reported in the literature ranges from 13 to 42
phoma (n = 3), mantle cell lymphoma (n = 1), and ex-               months and 20% to 65%, respectively.3,5–7,21–26 Our study
tranodal marginal zone lymphoma (n = 1) (data not                  showed similar results with a median survival of 4.2 years

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Li et al                                                           Am J Surg Pathol       Volume 37, Number 1, January 2013

and a 5-year OS of 46%. Previous studies have shown that       whether the presence of an angiocentric/angioinvasive
the following features are associated with poorer clinical     pattern could simply be related to biopsy specimens, with
outcome: age (> 60 y), male sex, presence of B-symptoms,       larger specimens more likely to have an angiocentric
elevated serum LDH, hemoglobin
Am J Surg Pathol        Volume 37, Number 1, January 2013                                                   Nasal ENKTL From the United States

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r   2012 Lippincott Williams & Wilkins                                                                                          www.ajsp.com |      23
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