Introduction
Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL) rarely presents
in the skin, with a relative frequency of less than 1% among primary cutaneous lymphomas.
1
It is most prevalent among Asian and South American natives.
2
Plaques or tumors located on the trunk are the most common presentation.
3
The prognosis is grave with a median survival time of 15 months from the time of diagnosis.
4
We present a case of CD56− ENKTL manifesting as 2 ulcers on the extremities of a white
man.
Case report
A 61-year-old white man presented with rapidly enlarging 7- 8-cm tender dome-shaped
nodules with central ulceration and necrosis on the left posterior calf (Fig 1) and
left forearm (not shown). The patient complained of fatigue and night sweats over
the prior week. The further examination was unremarkable with no other skin findings
or palpable lymphadenopathy.
Skin biopsy of the left forearm showed a diffuse and nodular lymphohistiocytic and
granulomatous infiltrate in the superficial and the reticular dermis centered around
skin appendages and blood vessels (angiocentricity) extending in subcutaneous adipose
tissue (Fig 2, A and B). Repeat biopsy 1 month later found a thinned epidermis with
impending ulcer with extensive area of necrosis, lymphocyte exocytosis, basal vacuolization,
and Civatte bodies (Fig 2, C). The dermis showed diffuse sheets of monotonous medium-sized
cells with hyperchromatic nuclei that extended into the epidermis and included numerous
(about 25%) large atypical lymphocytes (Fig 2, D). The infiltrate consisted of predominantly
T cells and some CD20+ B cells (Fig 3). Epstein-Barr virus (EBV)-encoded small RNAs
(EBER) were positive in approximately 75% of the infiltrate. The atypical lymphocytes
stained positively with CD2 and CD3 and exhibited loss of CD7 expression. Although
there were many CD4 (about 75%) and fewer CD8 (about 25%) cells, the precise phenotype
of the neoplastic cells was difficult to ascertain because of the numerous admixed
reactive T cells. BF-1 was positive in about 75% of cells. LCA, TIA-1, and granzyme
were positive in 50% of cells. CD5 highlighted background T cells. Ki-67 stained about
50% of the infiltrate. CD30 stained about 30% of the cells. FOXP3 and CD123 stained
about 10% of cells. CD56 and CD34 were negative and CD57 stained rare cells. Southern
blot did not detect T-cell receptor (TCR)-β chain rearrangement in the sample from
the left forearm, and TCR-γ chain rearrangement was indeterminate with polymerase
chain reaction in the repeat biopsy owing to an inhibitor preventing amplification.
EBV serology found significant elevation of VCA IgG antibody (>750 U/mL) and EBV nuclear
antigen IgG (537 U/mL). Bone marrow examination was negative for lymphoma involvement.
Further evaluation and subsequent staging included a positron emission tomography
(PET)/computed tomography (CT) scan, which found increased uptake in the left calf
at the place of the original tumor as well as in tonsils and spleen (Fig 4). Enlarged
lymph nodes were found in the cervical regions bilaterally; left superior mediastinum;
and the retroperitoneal, splenic, and bilateral inguinal regions. An ear, nose, and
throat examination was not performed but patient did not exhibit any of those symptoms.
Initially, after diagnosis, he was treated with radiation therapy to the lesion on
his left leg and arm, and R-CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone,
plus rituximab). After six cycles of R-CHOP, he exhibited complete clinical remission.
However, within 6 months, his disease recurred with subcutaneous nodules on his left
chest wall, left lateral thigh, and the right scrotum. He was restarted on R-ICE (ifosfamide,
carboplatin, and etoposide plus rituximab) for 3 cycles. His disease progressed despite
initiation of intrathecal chemotherapy with depocyt, carmustine, etoposide, cytarabine,
melphalan, and autologous stem cell transplant. He died 29 months after diagnosis.
Discussion
ENKTL, nasal type, is a rare and aggressive malignancy. ENKTL accounts for a small
minority of cutaneous lymphomas in the United States, where the condition is infrequently
seen, as most often it presents in Asia and South America.
5
The correct diagnosis of ENKTL depends on cutaneous and extracutaneous manifestations,
an involvement of the upper respiratory tract, histologic features, and immunophenotype.
6
The most commonly affected site is the nasal cavity and nasopharynx.6, 7 The skin
is involved in about 26% of cases.
8
Currently, the World Health Organization classification does not make a distinction
for primary cutaneous disease presentation.1, 3, 9 It is speculated that extranasal
and nasal presentations fall on a spectrum of the same disease, as PET/CT reveals
an occult primary tumor in most cases.
8
In concordance with this statement, our patient's PET/CT found tonsillar involvement
with enlarged regional cervical lymph nodes.
ENKTL classically shows an angiocentric and angiodestructive polymorphic infiltrate
of usually intermediate to larger lymphocytes with often elongated nuclei, sometimes
admixed with other inflammatory cells and often associated with necrosis.
10
Although the original biopsy found extensive lymphohistiocytic infiltrate that was
not further evaluated, the repeat biopsy found a more destructive pattern, typical
of ENKTL, with a perivascular and periadnexal lymphocytic infiltrate invading the
epidermis producing a large area of necrosis.
ENKTL shows CD2, CD56, and cytoplasmic CD3 positivity. CD56 was negative in our case.
CD56 is a marker for NK cells, expressed in a subset of CD4 and CD8 cells, and is
positive in 74% to 76% of cases of ENKTL.11, 12 A definite diagnosis of ENKTL in the
case of CD56 negativity requires EBV positivity and expression of the cytotoxic proteins
such as TIA1, granzyme B, or perforin.
3
Clonal TCR gene rearrangement is frequently nondetectable; however, a subset of tumors
in some series do show evidence of T-cell lineage.
13
In this case, the T/NK cell antigen expression, positive EBER staining, TIA-1 positivity,
granzyme B positivity, and a negative γδ stain confirm the diagnosis of CD56− ENKTL.
TCR gene rearrangement was indeterminate. Whether the ENKTL reported here is of T cell
or NK cell origin remains therefore undefined but does not impact the diagnosis.
Some investigators suggest that ENKTL with CD56 negativity should be described as
a separate subtype, and some postulate that CD56 negativity is associated with a more
aggressive clinical course.
14
In a retrospective study of 288 patients with early-stage upper aerodigestive tract
ENKTL,
14
the remission rate of the CD56+ group was 80.6%, whereas the CD56− group was 60.8%.
Further, CD56 negativity also was associated with a lower 5- and 10-year progression-free
survival. The case reported here, together with the previously published cases of
CD56− ENKTL with cutaneous involvement, have many similarities regarding their clinical
presentation and also appear to share a poor prognosis (Table I). All patients presented
with an indurated plaque with frequent ulceration on the lower extremity. Histologic
examination always found a heavy angiocentric lymphoid infiltrate with some degree
of angioinvasion.
The differential diagnosis of an isolated necrotic rapidly evolving ulcer on the lower
extremity is quite extensive, whereas EBV positivity narrows the differential diagnosis
to the following lymphomas and lymphoproliferative disorders: angioimmunoblastic T-cell
lymphoma (although, the EBV+ component is represented by the B cells and it is usually
not neoplastic; if it is neoplastic, then it is classified as diffuse large B-cell
lymphoma and not as angioimmunoblastic T-cell lymphoma); lymphomatoid granulomatosis;
EBV+ peripheral T-cell lymphoma, not otherwise specified; EBV-associated hemophagocytic
lymphohistiocytosis; aggressive NK-cell leukemia; and 2 variants of cutaneous chronic
active EBV infection—hydroa vaccinioforme–like lymphoproliferative disease (T/NK)
and severe mosquito bite allergy (NK). EBV+ lymphomas (both B- and T-) of many types
can be encountered in the setting of immune suppression (grouped as posttransplant
lymphoproliferative disorders). Immunohistochemistry, together with the morphologic
and clinical findings, are essential in establishing the correct diagnosis.
Ann Arbor staging for nodal lymphoma rather than the classification for mycosis fungoides
proposed by European Organization for Research and Treatment of Cancer is used for
staging of ENKTL.
15
Because of the rarity of ENKTL and lack of randomized, controlled trials, current
treatment protocols are consensus based.
15
For limited-stage disease (I/II), single modality such as radiotherapy or chemotherapy
(if a patient is sufficiently fit) is recommended. Advanced disease (III/IV) is managed
with a pegaspargase-based chemotherapeutic regimen (gemcitabine, pegaspargase, cisplatin,
and dexamethasone or DDGP)
16
with or without chemoradiation (radiation and platinum-based chemotherapy) according
to recent recommendations.
17
Our patient was treated 6 years ago initially with R-CHOP, which was prior to the
DDGP regimen being reported. Clinical trials are an alternative option at any stage
of ENKTL. If the patient is eligible, hematopoietic stem cell transplantation should
be considered.9, 10 Previous studies confirmed low success rates with anthracycline-containing
regimens. The overexpression of P-glycoprotein in tumor cells is deemed to be the
cause of chemoresistance and early relapse.
18
In concordance with those data, 3 of 5 CD56− ENKTL patients responded poorly to CHOP
(Table I). Two of 5 patients had some response to SMILE (L-asparaginase, ifosfamide,
methotrexate, etoposide, and dexamethasone). L-asparaginase–based regimens such SMILE
have been explored previously for advanced-stage and relapsed/refractory ENKTL, and
significant responses were observed.
19
Recently, pegaspargase-based chemotherapeutic regimens were proposed as advantageous
for pretreated ENKTL.
16
Our patient was treated with localized radiation, R-CHOP, R-ICE, intrathecal chemotherapy,
and autologous stem cell transplant. He survived only 29 months after diagnosis, which
is almost twice as long as reported median overall survival.
Interestingly, R-CHOP, in the case of our patient, provided a 6-month remission. There
is a modern notion to include B-cell depletion strategies in the treatment of EBV+
lymphoproliferative disorders, not of B-cell origin, based on the fact the EBV is harbored
mainly in resting B lymphocytes.
20
During the T lymphocyte depletion, EBV-infected B cells have a higher potential for
proliferation because of the diminishing of suppressive mechanisms. It would be interesting
to know if a combination of rituximab with pegaspargase-based chemotherapy would improve
overall survival, although its relevance in a case such as this in which the EBV is
at least largely in the T-cells is uncertain.
Cutaneous manifestations of ENKTL must be considered in the case of rapidly progressing
cutaneous ulcers even if the infiltrate is CD56−.