REVIEWS

Primary cutaneous aggressive epidermotropic CD81

T-cell lymphoma: Proposed diagnostic criteria and
therapeutic evaluation
Ahmad Nofal, MD,a M. Yousry Abdel-Mawla, MD,a Magda Assaf, PhD,b and Eman Salah, MSca
Zagazig, Egypt
Primary cutaneous aggressive epidermotropic CD81 T-cell lymphoma is a rare cytotoxic lymphoma
characterized clinically by aggressive behavior and histologically by prominent epidermotropism of atypical
CD81 lymphocytes. Despite the continuous addition of new case reports, no definite diagnostic criteria have
been established, and an optimum treatment is still awaiting. Herein, we study and analyze the different
clinical, histopathological, and immunohistochemical features described in the reported cases. Different
therapeutic modalities and their impact on the prognosis of the tumor are also evaluated and presented. We
propose two sets of diagnostic criteria. The first comprises constant clinical, histopathological, and
immunohistochemical features that are always present in every case, and the combination of which is
necessary for the diagnosis. The second set helps to avoid missing cases and includes variable features that
may be present in some cases, and to which any emerging finding could be added. Although different
therapeutic options have been used, either as single agents or in combinations, there is no standard therapy
for primary cutaneous aggressive epidermotropic CD81 T-cell lymphoma and the tumor still represents a
therapeutic challenge with very poor prognosis. ( J Am Acad Dermatol 2012;67:748-59.)
Key words: aggressive behavior; CD81 cytotoxic T cells; cutaneous lymphoma; diagnostic criteria;
epidermotropism; poor prognosis; therapeutic evaluation.

rimary cutaneous aggressive epidermotropic

CD81 T-cell lymphoma is a rare subtype of
cutaneous T-cell lymphoma (CTCL) characterized by widely distributed ulcerated lesions,
epidermotropic infiltrates of CD81 cytotoxic T cells,
aggressive course, high tendency to spread to extranodal sites, poor response to conventional therapies
of classic CD41 CTCL, and unfavorable prognosis.1-3
Primary cutaneous aggressive epidermotropic
CD81 T-cell lymphoma, which represents less than
1% of all cases of CTCL, has been classified as a
nonspecific, provisional entity according to the
World Health Organization (WHO)/European
Organization for Research and Treatment of Cancer
(EORTC) classification on 2005 and the fourth edition of the WHO classification on 2008.4,5

From the Departments of Dermatologya and Pathology,b Faculty

of Medicine, Zagazig University.
Funding sources: None.
Conflicts of interest: None declared.
Accepted for publication July 27, 2011.
Reprint requests: Ahmad Nofal, MD, 3 Abtal-Alfaloga St, Mitghmr,
Dakahlia, Egypt. E-mail: ahmadnofal5@hotmail.com.
Published online January 9, 2012.
0190-9622/$36.00
2011 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2011.07.043

748

Abbreviations used:
CTCL:
cutaneous T-cell lymphoma
EORTC: European Organization for Research and
Treatment of Cancer
FDA:
Food and Drug Administration
IL:
interleukin
MF:
mycosis fungoides
PUVA:
psoralen plus ultraviolet A
UV:
ultraviolet
WHO:
World Health Organization

Since its first description by Berti et al6 in 1999,

about 45 cases have been reported in the literature
(Table I).6-29 Although it has been proposed as a
distinct clinicopathological entity,6 no definite diagnostic criteria have been established, and an optimum treatment is not yet determined. Therefore, the
tumor still represents a diagnostic and therapeutic
challenge. Herein, we review the different aspects of
the tumor, suggesting two sets of diagnostic criteria
and evaluating the different current and future therapeutic modalities.

CLINICAL FEATURES
Primary cutaneous aggressive epidermotropic
CD81 T-cell lymphoma usually occurs in elderly
patients, and most (30 of 45) of the affected patients

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are male. Clinically, the disease usually manifests as

IMMUNOHISTOCHEMISTRY
rapidly progressing, widely distributed papules,
Expression of CD81/CD4e phenotype is the only
patches, plaques, nodules, and tumors, often with
constant immunohistochemical finding in all cases of
central necrosis, ulceration, or crustation (Fig 1). The
aggressive CD81 epidermotropic lymphoma (Fig
tumor is characterized by a short history, and
4),1-3 however, it should be noted that CD8 positivity
unlike classic mycosis fungoides (MF), it does not
is present in other well-defined, indolent types of
follow the typical progression of the lesions through
CTCL such as pagetoid reticulosis and CD81 MF.
patch, then plaque, and fiTherefore, the diagnosis of
nally tumors. There is no
this aggressive tumor cannot
CAPSULE SUMMARY
specific distribution of the
be based on this item alone,
lesions, however acral acbut in association with other
Primary cutaneous aggressive
centuation is commonly obclinical and histopathologiepidermotropic CD81 T-cell lymphoma is
served. Oral involvement,
cal findings. Although not
an extremely rare subtype of cutaneous
which is commonly reported
reported in every case, CD3,
T-cell lymphoma characterized by
in these patients, adds to the
CD45RA, bF-1, and T-cell inaggressive clinical behavior and
severity and aggression of
tracellular antigen-1 are usuproliferation of epidermotropic CD81
the tumor and indicates
ally positive in aggressive
T cells.
poor prognosis.1-6 Because
CD81 epidermotropic lymThe study presents a summary of the
of the widespread and ulcerphoma. Similarly, a high
reported cases, suggests new diagnostic
ative nature of the lesions,
ki-67 proliferation index is
criteria, and evaluates current and future
patients usually seem in a
also demonstrated in most
therapeutic options.
bad general condition that
cases.4-6 On the other hand,
may interfere with their
CD30, and CD45RO are alThe proposed diagnostic criteria help to
usual daily activities.3,6,19,23
most negative, however two
more precisely define this rare entity and
Uncommonly, this aggrescases of lymphomatoid pahopefully will lead to earlier diagnosis
sive tumor may present with
pulosis after an aggressive
and treatment.
superficial
hyperkeratotic
clinical course have been repatches
and
plaques
cently categorized as CD301
resembling clinically pagetoid reticulosis of the
variants of primary cutaneous aggressive epidermoKetron-Goodman type,3 with widespread annular
tropic CD81 T-cell lymphoma.31,32
20
erythematous scaling patches ; multiple maculoCD2, CD5, CD7, CD15, and CD56 showed variapapular eruption on the hands, feet, and face16; and
ble expression profiles.3-6,20,24 Epstein-Barr virus
pyoderma gangrenosumelike lesions.23
testing usually reveals negative expression, and
T-cell receptor-g rearrangement demonstrates
HISTOPATHOLOGY
T-cell origin and clonality.2-4
Although the histopathologic features of primary
cutaneous aggressive epidermotropic CD81 T-cell
lymphoma are not pathognomonic, two constant
DIFFERENTIAL DIAGNOSIS
MF, including classic cases showing a CD41
features are always present, with variable extent, in
phenotype and those expressing the unusual CD81
all reported cases. The first constant feature is
phenotype, represent the most important differential
epidermotropism that is often prominent, particudiagnosis of primary cutaneous aggressive epiderlarly in the basal cell layer (Fig 2), seen throughout
motropic CD81 T-cell lymphoma that characteristithe different stages of the disease and it usually
cally shows an aggressive clinical behavior3-6
follows a pagetoid or linear pattern. The second
(Table II).
feature is the presence of dermal infiltrate that
One of the closely similar conditions that shares
consists of variably sized atypical lymphocytes,
many features with aggressive epidermotropic CD81
arranged in nodular or diffuse pattern and usually
T-cell lymphoma is the Ketron-Goodman type of
extending deep into the dermis down to the subcupagetoid reticulosis; some authors3-5 have considtaneous fat (Fig 3).3-6 Other features are variably
present in some reported cases such as epidermal
ered that these cases probably represent examples of
changes in the form of acanthosis or atrophy; keratthis aggressive tumor before being characterized and
inocyte necrosis with or without ulceration; and,
described by Berti et al.6
Another important differential diagnosis is the
rarely, blistering, angiocentricity, and angioinvasion;
indolent types of CD81 CTCL such as CD301 primary
rimming of adipocytes; and destruction of adnexal
cutaneous
anaplastic
large-cell
lymphoma,
skin structures.4,11,12,30
d

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Table I. Summary of reported cases

Patient
No.

Age, y

Sex

Clinical presentation*

1-8

31-81

5M/3F

68

10

48

11-15

48-74

2F/3M

16

72

17-20

33-82

4M

21-25

37-80

4M/1F

26

39

Widespread patches,
plaques,
papulonodular
lesions, and tumors
with ulceration
Oral involvement in
3 patients
Widespread ulcerated
or crusted plaques
and nodules
Widespread, wellcircumscribed dull
red plaques with
central necrosis
Widespread
papulonodular
lesions with central
ulceration and oral
involvement in 2
patients
Widespread
erythematous
plaques and tumors
with tongue
involvement
3 Patients presented
with widespread
plaques and nodules
with hemorrhage and
central ulceration
One patient presented
with ulcerated
nodular lesions on
right leg
Widespread plaques
and tumors
commonly showing
ulceration
One patient had just
solitary ulcerating
tumor
Widespread ulcerative
papules and nodules,
oral involvement, and
sarcoidosis

27

70

28

42

Ulcerated nodules over

nose and forehead,
and multiple purpuric
papules over
abdomen
Disseminated nodules
with ulceration,
necrosis, and
weight loss

Treatment

Outcome

Reference

Conventional CTCL
therapies, TSEBT,
polychemotherapy,
allogenic BMT

DOD with mean

survival of 32 mo

Berti et al6

Multiagent
chemotherapy

DOD

Fujiwara et al7

Polychemotherapy;
MACOP-B and MOPP

DOD after 4 mo
of diagnosis

Urrutia et al8

Conventional CTCL
therapies, TSEBT
isotretinoin,
autologous BMT

4 DOD/1 alive

Agnarsson et al9

PUVA, localized
radiotherapy, and
extracorporeal
photophoresis

DOD 12 mo after
initial presentation

Quarterman et al10

PUVA and nitrogen

mustard CHOP,
TSEBT, interferon
alfa-2, and etretinate

DOD with mean

survival of 22.5 mo

Santucci et al11

Patient with solitary

lesion was given
local radiotherapy
Not mentioned for
other 4 patients

3 Patients DOD
within 6-36 mo
2 Patients were alive
for 7 and 8 mo at
last follow-up

Massone et al12

PUVA, topical
bexarotene,
methotrexate,
and multiagent
chemotherapy
Not started

Poor therapeutic
response with
disease progression

Gelfand et al13

DOD 21 mo after
onset of disease

Marzano et al14

Multiagent
chemotherapy

DOD 4 mo after
initiation of therapy

PoszepczynskaGuign

e et al15

Continued

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Table I. Contd
Patient
No.

Age, y

29

25

30

33

31

72

32

44

33

68

34

65

35

25

36

19

37

83

38-40

53-77

3M

41-42

70,80

2M

Sex

Clinical presentation*

Spreading
maculopapular plane
wartelike eruption
on hands, feet,
and face
Widespread ulcerated
tumors with marked
deterioration of
general condition
Ulcerated lesion at ear
pinna

Widespread verrucous
hyperkeratotic lesions
and ulcerated
plaques
Widespread annular
erythematous scaling
patches and tumors
with ulceration
Widespread annular
erythematous
patches and plaques
with ulceration

Widespread ulcerated
and hemorrhagic
plaques and nodules
Widespread, multiple
pyoderma
gangrenosumelike
lesions
Widespread patches
and plaques covering
80% of skin surface
Peripheral blood
involvement
Widespread ulcerated
red plaques
associated with
prolonged history
of psoriasis
Widespread ulcerated
plaques and tumors
with tongue
involvement in
1 patient

Treatment

Outcome

Reference

Patient refused further

investigations and
treatment

Patient was lost to

follow-up

Kim et al16

CHOP

DOD after relapse

Du-Thanh et al17

Localized radiotherapy
resulted in complete
regression of
tumor
8 Cycles of CHOP plus
allogenic peripheral
blood stem cell
transplantation
6 Cycles of CHOP in
parallel with TSEBT

Patient remained well

without recurrence
for 18 mo after
treatment
Patient remained alive
without new skin
lesions 17 mo after
transplantation
DOD 7 mo after
diagnosis

Fika et al18

Oral bexarotene, topical

nitrogen mustard,
PUVA, interferon alfa,
local electron beam
therapy, and
extracorporeal
photophoresis
Hyper-CVAD
chemotherapy

Patient showed
stability for 6 mo
before severe CNS
involvement; final
outcome was not
mentioned

Introcaso et al21

DOD after 9 mo

Csomor et al22

4 Cycles of CHOP gave

partial response

DOD after 22 mo

Wang et al23

Patient refused
treatment

DOD few days after

diagnosis

Benetatos et al24

Interferon alfa-2a, PUVA,

systemic steroids,
gemcitabine

DOD within 8-9 mo

of presentation

Weenig et al25

Clobetasol under
occlusion, nitrogen
mustard, topical and
oral bexarotene,
localized
radiotherapy, TSEBT,
hyper-CVAD
chemotherapy

First patient DOD

2 mo after starting
chemotherapy
Second patient was
well controlled on
oral bexarotene at
last follow-up

Gormley et al26

Liu et al19

Yoshizawa et al20

Continued

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Table I. Contd
Patient
No.

Age, y

43

64

44

58

45

38

Sex

Clinical presentation*

Abrupt onset of
widespread plaques
and tumors with
ulceration
Widespread, multiple
infiltrated and
ulcerated plaques
Extensive painful
ulcerative plaques
and tumors with
central necrosis

Treatment

Outcome

Reference

Not mentioned

DOD after 5.5 mo

Weaver et al27

Patient refused
chemotherapy and
was treated with oral
corticosteroids only
TSEBT, gemcitabine,
autologous BMT,
alemtuzumab,
lenalidomide

DOD after 2 y

Ohmatsu et al28

Patient was under

palliative treatment
on last follow-up

Webber et al29

BMT, Bone-marrow transplantation; CHOP, cyclophosphamide, hydroxydoxorubicin, Oncovin, prednisone; CNS, central nervous system;
CTCL, cutaneous T-cell lymphoma; CVAD, cyclophosphamide, vincristine, Adriamycin (doxorubicin), dexamethasone; DOD, died of disease;
F, female; M, male; MACOP-B, methotrexate, Adriamycin, cyclophosphamide, Oncovin, prednisone, bleomycin; MOPP, nitrogen mustard,
Oncovin, procarbazine, prednisone; PUVA, psoralen plus ultraviolet A; TSEBT, total skin electron beam therapy.
*All patients showed systemic involvement during course of their disease except those presenting by limited disease and nonaggressive
course such as cases 25, 29, and 31, in which we do not believe that they are true examples of primary cutaneous aggressive epidermotropic
CD81 T-cell lymphoma.

lymphomatoid papulosis, nasal and extranasal natural killer/T-cell lymphoma, subcutaneous panniculitiselike T-cell lymphoma, and cutaneous g/d T-cell
lymphoma.2,6 These subtypes of CTCL share many
histologic and immunohistochemical similarities
with primary cutaneous aggressive epidermotropic
CD81 T-cell lymphoma, which can be differentiated
on a clinical basis by its characteristic widely distributed and ulcerated lesions, highly aggressive behavior, and high tendency to systemic spread. An
accurate clinicopathological correlation is crucial in
this setting to avoid overdiagnosis that might lead to
overtreatment for nonaggressive subtypes of CTCL
that usually respond to conventional skin directed
therapies such as psoralen plus ultraviolet (UV)
A (PUVA), in contrast to the aggressive epidermotropic CD81 CTCL that often requires aggressive
polychemotherapy.5,6,26,31

METASTATIC SPREAD

Primary cutaneous aggressive CD81 epidermotropic T-cell lymphoma has a high tendency to
systemic spread to extracutaneous sites such as
central nervous system, lung, and testis, while
lymph nodes are usually spared in contrast to classic
MF.2,3,6 Cases presenting with disseminated ulcerated plaques and nodules that behave aggressively
to involve most of the body surface area within a
short period are more associated with metastatic
spread, ie, the higher the severity of the clinical
lesions, the higher the liability to systemic
spread.6,26 The difficulty in diagnosis of this recently

recognized and poorly defined tumor results in late

diagnosis and therapy that might lead to systemic
spread. The morphology of the infiltrating atypical
lymphocytes, whether small or large, was not found
to have a definite role in the high metastatic potential of the tumor.26 Santucci et al11 have suggested
that the metastatic pattern reported in this aggressive lymphoma may be related to CD56 positivity,
however many cases, including those reported by
Berti et al,6 showed metastatic spread in spite of
negative CD56 expression. Also, the angiocentricity
and angioinvasion, the expression of CD15, and the
CD7e/CD21 phenotypes have been proposed to be
associated with higher incidence of systemic
spread.3,5,6,20

PROGNOSIS
Although the reported cases of aggressive epidermotropic CD81 CTCL are few, the prognosis in
most of these patients is very poor; only 7 of 45 were
found alive and well on their last follow-up (Table I).
The median survival in the first 8 cases reported by
Berti et al6 was 32 months, whereas it was only 22.5
months in the 4 patients reported by Santucci et al.11
An average 5-year survival of 18% as compared with
88% in the more indolent MF was reported in
European cutaneous lymphoma groups.4,33 This
poor outcome may be attributed to the highly
aggressive clinical lesions that usually resulted in a
rapid metastatic spread, a lower response rate to
chemotherapy, and a higher incidence of
relapses.3,5,6,26

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Fig 2. Prominent epidermotropism at basal cell layer.

(Hematoxylin-eosin stain; original magnification: 3200.)

Fig 1. Typical clinical lesions at different stages of evolution. A, Erythematous papules, patches, and plaques with
few lesions showing central necrosis and crustation.
B, Well-defined erythematous plaques with prominent
central necrosis and crustation.

It was also observed that expression of a CD2e/

CD71 phenotype has been associated with rapid
progression, aggressive behavior, and consequently
poor prognosis, whereas cases showing a CD21/
CD7e phenotype are associated with a less aggressive course and a relatively better prognosis as is the
case with the CD81 MF.3,9,26,27 Expression of a CD15
phenotype has also been proposed to be associated
with poor prognosis.20,24 However, because these
observations were not consistent in all reported
cases, and simply were not done in every case, no
clear-cut significance of these immunophenotypes
could be established. Cases associated with deep
infiltration, angiocentricity, and angioinvasion have
also been observed to be associated with aggressive
clinical behavior and a poor prognosis.1,3,6,26

Fig 3. Dermal infiltration by large atypical lymphocytes.

(Hematoxylin-eosin stain; original magnification: 3400.)

CLASSIFICATION
Because of its rarity, its relatively variable clinical
presentations, and its closely similar histologic and
immunohistochemical features to some CD81
CTCL,3,5,26 primary cutaneous aggressive epidermotropic CD81 T-cell lymphoma has been classified a
provisional, nondistinct entity according to the
last WHO/EORTC classification for cutaneous
lymphoma.4

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of primary cutaneous aggressive epidermotropic

CD81 T-cell lymphoma as a specific or distinct entity.

DIAGNOSTIC CRITERIA

Fig 4. Immunohistochemistry showing epidermal and

dermal CD81 atypical lymphocytes.

Some authors have attributed this classification to

the assumption that the tumor displays characteristic
histopathological features without distinct clinical
presentation, outcome, or both.34 We do not agree
with this concept because the clinical features
reported in these cases are much more specific2
than the histologic and immunohistochemical features that share many similarities with indolent CD81
CTCL, as previously mentioned.
In support of our view, Diwan and Evan3 have
proposed that primary cutaneous aggressive epidermotropic CD81 lymphoma is so characteristic in its
clinical behavior that makes its separation into a
distinct entity to have validity. Berti et al6 and Csomor
et al22 have also described the tumor as a distinct
disease that is characterized by aggressive clinical
behavior, special histologic and immunohistochemical features, poor response to therapy, and unfavorable diagnosis.
We believe that the ulcerated, widely disseminated lesions with characteristic aggressive clinical
behavior; the prominent epidermotropism by atypical CD81 T lymphocytes; the high metastatic tendency; the poor response to conventional therapies
used for CD41 CTCL; and the bad prognosis usually
experienced in these patients merit the consideration

As regards the diagnosis of primary cutaneous

aggressive epidermotropic CD81 T-cell lymphoma,
there is no single criterion that is pathognomonic
alone for the disease. It is only the combination of
clinical, histopathological, and immunohistochemical features that could establish the diagnosis. We
suggest two sets of diagnostic criteria (Table III) to
simplify the diagnosis, to avoid missing cases, and to
allow early and prompt therapy of this aggressive
tumor. The first set comprises constant clinical,
histopathological, and immunohistochemical features that almost always present in every case, and
the second set includes variable features that were
reported in some patients, and to which any emerging finding could be added.
We believe that the clinical features of this aggressive tumor are critical for its diagnosis because of the
multiple histologic and immunohistochemical overlaps with other indolent types of CD81 CTCL such as
pagetoid reticulosis, CD301 primary cutaneous anaplastic large-cell lymphoma, subcutaneous panniculitiselike T-cell lymphoma, and rare cases of MF.1,3,6
We propose that two clinical features must be present to define the tumor precisely and to differentiate
it from other closely similar variants of CTCL. These
features include disseminated ulcerated papules,
plaques, nodules, and/or tumors without longstanding precursor lesions and an aggressive behavior that leads to rapid progression of the lesions over
the skin surface and usually to extracutaneous sites.
Accordingly, we suggest that patients presenting
single or few nonaggressive lesions that remain as
such throughout the course of the disease and who
responded well to conventional CD41 CTCL therapies should not be considered to have aggressive
epidermotropic CD81 lymphoma even if showing its
typical histologic and immunohistochemical features. The clinical significance of this suggestion is
to avoid the use of aggressive and exhaustive
polychemotherapy for nonaggressive subtypes that
usually respond to conventional, nonaggressive
therapies such as localized radiotherapy and PUVA.
In this context, we believe that some of the
reported cases in the literature do not fit well with
the aforementioned characteristic clinical lesions and
course and so cannot be considered as true examples
of aggressive epidermotropic CD81 T-cell lymphoma, but rather represent indolent forms of
CD81 CTCL. These include patient 25 reported by
Massone et al12 and patient 31 reported by Fika
et al,18 who presented only one lesion throughout

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Table II. Differences between mycosis fungoides and primary cutaneous aggressive epidermotropic CD81
T-cell lymphoma
Mycosis fungoides

History
Clinical features
Symptom
Precursor lesions
Central ulceration
Extent
Mucosal involvement
General condition
Histopathology
Epidermotropism
Keratinocyte necrosis
Depth
Adnexal structures
Angiocentricity and angioinvasion
Immunophenotype
CD4
CD8
Course
Metastatic spread
Incidence
Nodal
Extranodal
Therapy
Conventional therapy for CD41 CTCL
Systemic chemotherapy
Prognosis

Primary cutaneous aggressive epidermotropic

CD81 T-cell lymphoma

Long, usually years

Short, weeks to months

Itching is common
Usually patches at first
Uncommon
Localized or generalized
Very rare
Usually good

Pain is common
Plaques and tumors from start
Very common
Generalized
Common
Usually bad

Early, less pronounced

Rare
Less deep
In syringotropic and folliculotropic
variants
Very rare

All stages, marked

More common
More deep to subcutaneous fat
Usually involved
Relatively common

1
Rarely positive
Indolent, even in CD81 cases

Always positive
Aggressive

Rare and late

Common
Lung, spleen, and liver

Common and early

Lymph nodes are usually spared
Lung, testis, and CNS

Usually effective
Rarely needed
Good

Not effective, some may worsen

Almost always needed
Poor

CNS, Central nervous system; CTCL, cutaneous T-cell lymphoma.

the long course of the disease without any cutaneous

or extracutaneous spread, and who responded completely to localized radiotherapy; these also include
case 29 reported by Kim et al,16 presenting asymptomatic, nonaggressive plane wartelike lesions in an
otherwise healthy patient who refused any more
investigation or treatment. Going with the same
concept, the two cases reported by Gormley et al26
cannot be considered as primary cutaneous aggressive epidermotropic CD81 lymphoma throughout
the first year of presentation where there were single
or very few indolent, nonaggressive lesions that did
not affect the general health of the patient or cause
metastatic spread. At that time they might only
represent indolent forms of CD81 CTCL such as
CD81 MF. Only when the lesions become necrotic,
rapidly progressing, widely distributed, and spreading to extracutaneous sites can the term aggressive
epidermotropic CD81 lymphoma be applied. This
raises the question about the possibility of transition
from one form (less aggressive) to another (more
aggressive) within the CTCL.25,26

On the other hand, the cases reported by Fujiwara

et al,7 Urrutia et al,8 Agnarsson et al9 in 1990, and
Quarterman et al10 in 1995 as being CD81 MF that
behaved aggressively can be considered as true
examples of primary cutaneous aggressive epidermotropic CD81 T-cell lymphoma because they
presented by almost the same clinicopathological
features of the first 8 cases described by Berti et al in
1999,6 and so they were included in the literature
review of the reported cases (Table I).

TREATMENT
Primary cutaneous aggressive epidermotropic
CD81 T-cell lymphoma represents a continuing
therapeutic challenge, and its optimum treatment
remains to be determined (Table IV). This may be
attributed to the paucity of reported cases and
consequently the absence of large randomized trials
necessary for evaluation of different therapeutic
regimens, particularly their long-term efficacy.
Another challenge against successful therapy of this
rare subtype of CTCL is its highly aggressive course

756 Nofal et al

Table III. Proposed diagnostic criteria

A. Constant features*
Clinical:
1. History: short; few weeks or months
2. Course: aggressive
3. Lesions: widespread papules, plaques, and tumors,
often ulcerated, without any precursor lesions
Histopathological:
1. Epidermotropism, often prominent
2. Nodular or diffuse infiltrates of pleomorphic T cells
Immunohistochemical:
1. CD81
2. CD4e
B. Variable featuresy
Clinicalz:
1. Pyoderma gangrenosumelike lesions
2. Pagetoid reticulosiselike superficial hyperkeratotic
patches and plaques
3. Annular erythematous scaling patches
Histopathological:
1. Spongiosis, blistering, and necrosis
2. Deep infiltration reaching subcutaneous fat with
rimming of adipocytes
3. Invasion and destruction of adnexal skin structures
4. Angiocentricity and angioinvasion
Immunohistochemical:
1. Variable expression profiles of CD2, CD5, CD7,
CD15, CD30, CD45, and CD56
*All of constant clinical, histopathological, and immunohistochemical
features must be present to establish definite diagnosis.
y
Variable features help to avoid missing cases.
z
These cases showed classic constant lesions, in addition to
uncommon variable features.

that is commonly associated with systemic spread

within short periods so that the treatment, in many
cases, may be delayed until metastatic spread has
occurred, leading to poor response even to the most
aggressive therapy.3,4,6,35
Conventional therapies for classic CD41 CTCL,
including topical steroids, topical nitrogen mustard,
topical bexarotene, UVB, PUVA, local radiotherapy,
and interferon alfa are usually ineffective.3-6,26,35
Primary cutaneous aggressive epidermotropic CD81
T-cell lymphoma that already exhibits a T-helper-1 cytokine profile19 may be worsened by the use of
interferons or other treatments that activate or augment T-helper-1 responses by increasing the recruitment and proliferation of CD81 T cells. Actually, in
the original report of Berti et al,6 rapid disease
progression was observed in 3 patients treated with
interferon or PUVA.1 This restricts the available therapeutic options, adding to the challenges associated
with the treatment of this aggressive tumor.1,3,6,26
Multiagent chemotherapy, particularly doxorubicinbased regimens such as cyclophosphamide,

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hydroxydoxorubicin, Oncovin, and prednisone

(CHOP) and the hyper-cyclophosphamide, vincristine, Adriamycin (doxorubicin), and dexamethasone
regimen (hyper-CVAD) that consists of alternating A
cycles (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and B
cycles (high-dose methotrexate and cytarabine), in 6
to 8 courses, is the most commonly used option for
patients with primary cutaneous aggressive CD81
epidermotropic T-cell lymphoma. 6-11,13-15,19-23,25,26
Intensified regimens such as methotrexate,
Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin (MACOP-B) have not shown a
survival advantage over CHOP.8,35 Generally, the
results of multiagent chemotherapy are unsatisfactory
and no available therapy seems to be curative because
the response is usually partial, and if complete is
associated with rapid relapse, in addition to the high
incidence of toxic effects, particularly myelosuppression and opportunistic infections.3-6,26,35,36
Gemcitabine is a purine analog that has been
associated with high response rates and relatively
low toxicities in the treatment of advanced-stage
CD41 CTCL, either as single-agent chemotherapy or
in combination with other agents.35,36 However, its
use in the reported cases of primary cutaneous
aggressive epidermotropic CD81 T-cell lymphoma
was not associated with remarkable response.25,29
Total skin electron beam therapy has been used in
many cases, either alone or in combination with
other agents such as oral retinoids, and was usually
associated with partial response.6,9,11,20 Some cases
have shown complete clearance of the lesions,
however long-term remission is not usually established and the tumor usually recurs within few
weeks.6,11,19,26
Bexarotene is a new synthetic rexinoid that selectively binds to the retinoid x receptor subfamily and
is formulated as either as capsule or a topically
applied gel.36 Oral bexarotene has been used as a
single agent,21 in combination with other modalities
such as total skin electron beam therapy, or for
postchemoradiotherapy refractory patients.26,29
Bexarotene is usually associated with partial remission of the tumor; however, one patient was well
controlled on oral bexarotene with no new emerging
skin lesions, but a long-term cure was not established.26 On the other hand, oral bexarotene has
been proposed to initiate the development of aggressive subcutaneous panniculitiselike T-cell lymphoma during treatment of S
ezary syndrome.37
Allogeneic or autologous transplantation is a
therapeutic option that might be considered in
appropriate candidates, particularly in cases
unresponsive or relapsed after multiagent

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Nofal et al 757

VOLUME 67, NUMBER 4

Table IV. Current and future therapeutic options for primary cutaneous aggressive epidermotropic CD81
T-cell lymphoma
Drug

Comment

Reference

Conventional CD4 therapies

Usually ineffective, either as single agents or in
Topical steroids
combination; may worsen
Topical chemotherapy
Topical retinoids and bexarotene
PUVA
Interferon alfa
Radiotherapy
Localized
Usually ineffective; produced clearance in patient 29, who
presented with single lesion
TSEBT
Partial or not long-lasting complete remission; usually used
as combination therapy
Oral rexinoids
Oral bexarotene
Associated with partial remission; better response is
achieved when combined with other modalities such as
TSEBT
Extracorporeal photophoresis
Uncommonly used; often ineffective
Systemic chemotherapy
Single agent:
Gemcitabine
A purine analog, used in 2 cases without success; its use as
combination therapy is under trial
Multiagent
CHOP
Most commonly used option; results are unsatisfactory,
Hyper-CVAD
associated with rapid recurrence; better response may
be achieved with BMT
MACOP-B
MOPP
Transplantation
Autologous or allogeneic
Promising; has been associated with complete remission in
1 patient; combination with chemotherapy in
appropriate candidates may improve outcome
New drugs
Monoclonal antibodies
Alemtuzumab
Anti-CD52 antibody; highly immunosuppressive with high
incidence of infections; used once in combination with
BMT, resulting in complete remission, followed by rapid
relapse
Immunomodulatory agents
Lenalidomide
Used once in relapsing late-stage disease without success
HDACI
Vorinostat
Recently FDA approved for CD41 CTCL; not used in any
reported cases
Fusion proteins
Denileukin diftitox
Recently FDA approved for CD41 CTCL; not used in any
reported cases
Folate analogs
Pralatrexate
Promising in PCTCL, not otherwise specified; not used in
any reported cases

6,9,10,11,13,14,21,25,26

18,21,26
6,9,11,20,26,29

11,21,26

10,21

25,29

6,9,11,13,15,17,19,23,25,26

6,9,19,29

29

29
26,36

26,36

32

BMT, Bone-marrow transplantation; CHOP, cyclophosphamide, hydroxydoxorubicin, Oncovin, prednisone; CTCL, cutaneous T-cell lymphoma;
CVAD, cyclophosphamide, vincristine, Adriamycin (doxorubicin), dexamethasone; FDA, Food and Drug Administration; HDACI, histone
deacetylase inhibitors; MACOP-B, methotrexate, Adriamycin, cyclophosphamide, Oncovin, prednisone, bleomycin; MOPP, nitrogen mustard,
Oncovin, procarbazine, prednisone; PCTCL, peripheral cutaneous T-cell lymphoma; PUVA, psoralen plus ultraviolet A; TSEBT, total skin
electron beam therapy.

chemotherapy.35,36 This option has proved efficacy

in the patient reported by Liu et al,19 who remained
alive, without new skin lesions, 17 months after her

allogeneic stem-cell transplantation. On the other

hand, partial or complete response that is followed
by relapse and death have been reported in other

J AM ACAD DERMATOL

758 Nofal et al

cases.6,8,29 Some authors have recommended the

early use of combined intensive chemotherapy and
autologous stem cell transplantation, particularly in
younger patients who can tolerate the procedure to
achieve the most favorable prognosis.35
Promising new therapeutic modalities are under
active investigation for different types of CTCL,
particularly MF and S

ezary syndrome. These include
new histone deacetylase inhibitors, monoclonal antibodies, forodesine, fusion proteins, proteasome
inhibitors, and immunomodulatory agents, such as
lenalidomide. With emerging reports of new cases,
these drugs may prove efficacy in the treatment of
primary cutaneous aggressive epidermotropic CD81
T-cell lymphoma, either as single agents or in combination with other modalities.35,36 Histone deacetylase inhibitors such as vorinostat have been shown to
induce differentiation and apoptosis in various tumors through a decrease in the transcription process.
Vorinostat is the first histone deacetylase inhibitor
approved by the US Food and Drug Administration
(FDA) for the treatment of CD41 CTCL.26,35
Denileukin diftitox is a fusion protein combining
the receptor binding domain of interleukin (IL)-2
and the diphtheria toxin. It has recently been approved by FDA for patients with relapsed CTCL
whose tumors express the IL-2 receptor subunit
(CD25).35,36 Neither vorinostat or denileukin diftitox
have been used in any of the reported cases of
primary cutaneous aggressive epidermotropic CD81
T-cell lymphoma; however, they may prove effective
in the near future.
Alemtuzumab, a humanized CD52 monoclonal
antibody, has shown activity in some T-cell malignancies such as advanced-stage CTCL, both as a
single agent and in conjunction with other agents.
Alemtuzumab is an extremely immunosuppressive
drug that is associated with marked neutropenia and
a reduction in T cells, therefore an appropriate
antibiotic and virostatic prophylaxis is required.35
Alemtuzumab has been used in combination with
reduced-intensity autologous bone-marrow transplantation in the case reported by Webber et al,29
resulting in complete remission that is followed by
rapid relapse after 60 days.
Lenalidomide, a new well-tolerated, immunomodulatory agent that has been recently investigated
for the treatment of MF and S

ezary syndrome. It has
been used, in combination with other agents, in one
case of aggressive epidermotropic CD81 T-cell lymphoma without success.29
Pralatrexate is a folate analog that has enhanced
activity through more efficient internalization and
intracellular accumulation when compared with
methotrexate. It has been emerged as a promising

OCTOBER 2012

new agent in the treatment of peripheral T-cell

lymphoma, not otherwise specified38; however, it
has not been used in any of the reported cases of
primary cutaneous aggressive epidermotropic CD81
T-cell lymphoma.
In summary, there is a major need for large,
prospective, randomized trials to evaluate novel
therapies in primary cutaneous aggressive epidermotropic CD81 T-cell lymphoma; to explore the
efficacy of combination regimens with potential
synergism; and to allow statistically significant evaluation of the different treatment options.26,37
However, the rarity of the reported cases, as previously mentioned, represents the major challenge
against achievement of these goals.

CONCLUSION
Primary cutaneous aggressive epidermotropic
CD81 T-cell lymphoma is a rare and very aggressive
variant of CTCL. There is no single criterion that is
pathognomonic alone for the tumor. Integration of
the constant clinical, histologic, and immunohistochemical features could only establish the diagnosis.
Variable features help to avoid missing cases and
could include any emerging feature. We propose that
the presence of rapidly progressing, widely distributed ulcerated plaques, nodules, and tumors, without long-standing precursor lesions, that usually
worsen the general condition of the patients, may
spread over a short period to extracutaneous sites,
and show both epidermal and dermal infiltration by
atypical CD81/CD4e lymphocytes strongly suggest
the diagnosis of primary cutaneous aggressive epidermotropic CD81 T-cell lymphoma.
Although multiple therapeutic options have been
tried, there is no definite successful therapy available
and the tumor still represents an extremely therapeutic challenge. Emerging reports and efforts may
help to define precisely the different clinical, histopathological, and therapeutic aspects of this aggressive subtype to allow early diagnosis, definite
treatment, and better prognosis.
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