J Cutan Pathol 2014
doi: 10.1111/cup.12353
John Wiley & Sons. Printed in Singapore
© 2014 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd
Journal of
Cutaneous Pathology
Review
A review of the solitary cutaneous
T-cell lymphomas
Cutaneous T-cell lymphomas (CTCL) account for almost 65-92%
of all cutaneous lymphomas, many of which usually present with
multiple lesions. However, a number of well-recognized and rare
types of CTCL, including mycosis fungoides, can present in
isolated fashion. These solitary lesions often run a relatively
indolent clinical course but often pose diagnostic difficulties. We
review histopathologically challenging solitary cutaneous T-cell
lymphomas, including criteria for diagnosis, clinical course and
prognosis, particularly for primary cutaneous CD4+
small/medium pleomorphic lymphoma and indolent CD8+
lymphoid proliferation of acral sites. In addition, we suggest an
algorithm and nomenclature to aid in the diagnosis of such
problematic lesions.
Keywords: solitary mycosis fungoides, pagetoid reticulosis, indolent
CD8+ lymphoid proliferation of acral sites, primary cutaneous
CD4+ small/medium pleomorphic lymphoma
Ally MS, Robson A. A review of the solitary cutaneous T-cell
lymphomas.
J Cutan Pathol 2014. © 2014 John Wiley & Sons A/S. Published by
John Wiley & Sons Ltd
Primary cutaneous T-cell lymphomas present
in the skin with no evidence of extra-cutaneous
involvement.1 Cutaneous T-cell lymphomas
(CTCL) account for almost 65–92% of all cutaneous lymphomas,2 of which, mycosis fungoides
(MF) is the most common and characteristically
presents with multiple lesions. However, solitary
MF, including and distinct from pagetoid reticulosis (Woringer-Kolopp), is well documented;3
similarly, other well-characterized forms of
lymphoma can present as an isolated lesion.
Finally, a number of increasingly recognized
rarer CTCL commonly present with an isolated
lesion, including CD4+ small/medium pleomorphic T-cell lymphoma (SMPTCL) and indolent
CD8+ lymphoid proliferation of acral sites.4
Although it seems that these isolated lesions
Mina S. Ally1 and Alistair
Robson2
1
Department of Dermatology, Stanford
University School of Medicine, Redwood City,
CA, USA, and
2
St. John’s Institute of Dermatology,
St. Thomas’ Hospital, London, UK
Alistair Robson, FRCPath Dip RCPath,
St. John’s Institute of Dermatology, St. Thomas’
Hospital, Westminster Bridge Road, London SE1
7EH, UK
Tel: 0207 1887188
Fax: +44 207 1886382
e-mail: [email protected]
Accepted for publication December 16, 2013
run a relatively indolent clinical course, they
continue to pose diagnostic difficulty.
In this review, we present an overview of the
solitary cutaneous T-cell lymphomas that, in
our opinion, present the greatest challenge in
diagnosis and that have been emerging over the
last 5 years. We have excluded some of the more
clinically aggressive tumors that may present as
solitary lesions as they tend to be well recognized
and histopathologically and immunophenotypically distinct. We discuss the criteria for
diagnosis, particularly for primary cutaneous
CD4+ small/medium pleomorphic lymphoma
and indolent CD8+ lymphoid proliferation
of acral sites. Finally, we suggest an algorithm
to aid in the diagnosis of such problematic
lesions.
1
Review
Cutaneous lymphoma classification and review
The recent détente and concord between
the World Health Organization (WHO) and
European Organization for the Research and
Treatment of Cancer (EORTC) classifications
acknowledges the unique features of primary
cutaneous lymphomas, which differ greatly from
the nodal and other extranodal lymphomas.1,5
An accurate diagnosis of primary cutaneous
lymphoma requires the correlation of the clinical findings with the microscopic, immunophenotypic and genetic features. Given that the
majority of lymphomas usually present with multiple lesions it is difficult to make a diagnosis
of a specific cutaneous lymphoma when faced
with the clinical presentation of a solitary lesion.
Moreover, in the absence of multiple lesions the
surgical pathologist is frequently in difficulty in
determining whether an infiltrate is neoplastic
or reactive.
To date, of the solitary cutaneous T-cell
lymphomas reported in the literature, approximately 166 cases represent MF,3 231 represent
SMPTCL, 22 represent indolent CD8+ lymphoid proliferation and 62 represent pagetoid
reticulosis (Table 1).
Solitary MF
MF accounts for almost 50% of all primary cutaneous lymphomas and is characterized by multiple patches and plaques.1 Indeed, given that
the finding of multiple patches and plaques
is a defining feature it is somewhat contradictory to consider a solitary variant. Nevertheless,
since 1981, 166 solitary cases of MF have been
described that are distinct from pagetoid reticulosis, including 10 of the folliculotropic variant
(follicular MF)2,3,6 – 8 and 9 cases of syringotropic
MF.9 – 12
Clinical features
Solitary MF, clinically and histopathologically
resembles classic MF. Clinically, it presents as a
single erythematous scaly patch or plaque, in
non-sun-exposed areas.1 Solitary MF has been
reported to have an excellent prognosis,3,13,14
although recurrence of treated lesions has been
reported2,13,15 – 18 six of which occurred distant
from the site of the original lesion (Table 1). Two
of these distant recurrences presented as multiple lesions, but in both cases, there was complete
resolution with further treatment and no further
disease at follow-up.2 The other four cases presented as a unilesional recurrence.11,17 In addition, four cases of solitary MF have progressed
to further cutaneous involvement, three of which
had large cell transformation.2,8,16,19
Solitary lesions of follicular and syringotropic
MF are also clinically and pathologically indistinguishable from lesions seen in classical disease. Solitary folliculotropic MF presents as an
infiltrated patch, plaque or an isolated area of
follicular papules without prominent scaling,
usually in the head and neck area.2,6,8 Solitary
syringotropic MF usually presents with a single
erythematous, indurated plaque, often studded
with small pinhead-sized papules, in the trunk,
hip and thigh area,11,20 although cases have
been reported in the head and neck area.11,12
Alopecia is a prominent feature in both cases.11
There is still uncertainty about the relationship between these two MF subtypes, but they
often co-exist.6,11,20 When compared with classic MF, folliculotropic MF is typically associated
with a poorer prognosis.21 This is sometimes,8
but not always the case for solitary lesions.2,6
Syringotropic MF, however, has a prognosis similar to that of classic MF.22 Out of the nine solitary cases of syringotropic MF reported, one has
shown recurrence of the lesion distant from the
original site.11
Finally, the report of an EORTC workshop concerning granulomatous MF and granulomatous
slack skin (GSS) detailed one solitary example
of GSS.23 Recently, at the senior author’s institution, a case of GSS presented with a single
pendulous axillary skin fold, which was followed
Table 1. Number of reports of each solitary cutaneous T-cell lymphoma and reported instances of recurrence or disease progression
Cutaneous
lymphoma type
Solitary MF
Pagetoid reticulosis (Woringer-Kolopp)
SMPTCL
Indolent CD8+ lymphoid proliferation of
acral sites
Total cases
Cases with cutaneous/
systemic progression
166
62
231
22
4 (Cutaneous spread, 3 × large cell transformation)
1 (Cutaneous spread)
5 (Extracutaneous spread, one died of lymphoma)
0
*Recurrence occurred at the same site of the original lesions unless stated otherwise.
2
Cases with lesion recurrence
post-treatment*
15 (six distant from original site)
8 (1 distant from original site)
12
4 (one distant from original site)
Review
Fig. 1. A solitary plaque of granulomatous slack skin, affecting
the groin.
several years later with involvement of the groin
(Fig. 1).24 A recent report by Ally et al.3 of 15
cases suggested that the observation of solitary
MF might be expected, albeit exceptional, in
which the disease is simply found at an uncommonly early stage. The unsurprising excellent
prognosis of such cases indicates that therapy
should aim to be curative.
Histopathologic features
In solitary MF, microscopic sections show a superficial lymphoid infiltrate of epidermotropic and
atypical lymphocytes.20,25 Atypia is usually more
pronounced in the epidermotropic lymphocytes
than those in the dermis.26,27 Other histopathologic features include lining up of atypical
lymphocytes at the dermoepidermal junction,
Pautrier microabscesses and fibrotic changes in
the papillary dermis, none of which is specific
for the diagnosis of MF11 (Fig. 2). Indeed, Cerroni et al.’s13 series of 20 cases lacked many of
these features. Folliculotropic and syringotropic
MF are characterized by infiltration of atypical
lymphocytes within and around the hair follicle
and/or eccrine epithelium6,8 sometimes with
follicular mucinosis.20 However, atypia can be
minimal and distinction from idiopathic prior
to follicular mucinosis is problematic; follow-up
with repeated biopsies may be required. Thus,
in short, the histopathologic features of solitary
lesions of MF mimic the features of the classic
disease.
In the context of a solitary lesion, perhaps the
burden of proof for the diagnosis should be
particularly stringent; in Ally et al.’s3 series of 15
patients there were at least two of the following;
morphological and cytological features of MF,
Fig. 2. ’Lining up’ of atypical lymphocytes at the dermoepidermal junction and fibrotic changes in the papillary dermis are
noted in a solitary patch of mycosis fungoides involving the
thigh of a 75-year male (hematoxylin/eosin, ×100).
loss of T-cell associated antigens, T-cell clonality
and appropriate clinical appearance.
Immunocytochemistry
Immunophenotypically, solitary MF, like classic
MF, is usually a neoplasm of CD4+ T-helper
cells, although CD8+ and double negative
CD4−/CD8− variants have been described.28 In
addition, there may be variable antigen loss of
CD2, CD5 and CD7.3 These immunophenotypes
do not seem to affect prognosis.28,29
T-cell receptor gene analysis
T-cell receptor (TCR) gene rearrangements are
detected in approximately 57–71% of cases of
early MF,29 so solitary lesions might be expected
to have a similar or perhaps lower clonal prevalence. Out of the 166 cases of solitary MF
published, approximately 76 were tested for
TCR clonality, of which 45 cases had a clonal
TCR rearrangement.3,13,16,20,28,30 – 32 The detection of monoclonal TCR rearrangements does
not appear to be of prognostic impact.13,16,29
Pagetoid reticulosis (Woringer-Kolopp)
In 1939, Woringer and Kolopp reported a solitary plaque on the forearm of a 13-year-old
boy, which resembled MF. Since then, the
term pagetoid reticulosis was introduced, to
recognize the similarity between the atypical
epidermotropic cells in this disease and the
intraepidermal adenocarcinomatous cells of
Paget’s disease of the nipple.33 In the 2005,
WHO/EORTC classification of cutaneous lymphomas, pagetoid reticulosis is classified as a
3
Review
distinguish these cases from lymphomatoid
papulosis (LyP) type D (Fig. 4B) or the more
recently described variant of LyP associated
with 6p25.3 rearrangements, rare cases of MF
with this pattern and aggressive epidermotropic
CD8+ T-cell lymphoma.43 In addition, microscopic distinction of pagetoid reticulosis from
some cases of CD8+ pityriasis lichenoides et
varioliformis acuta cases may be challenging,
especially when only sparse clinical data are
provided.44
Fig. 3. A well-circumscribed, hyperkeratotic plaque of pagetoid
reticulosis.
variant of MF, despite having distinct clinical
and histopathologic features.14,34 – 36
Clinical features
The typical lesion of pagetoid reticulosis is a
solitary, slow growing, well circumscribed, psoriasiform or hyperkeratotic plaque1,20,37 (Fig. 3).
In some cases, patients present with multiple
lesions.38 Pagetoid reticulosis typically affects
the distal extremities,33 although, lesions on
the trunk39 and even the tongue38 have been
described. Pagetoid reticulosis can affect any age
group including young children40 and usually
has an indolent clinical course, although there
is potential for dissemination and malignant
behavior.20,41 Some cases have been associated
with the development of MF several years after
the development of pagetoid reticulosis,38,42
highlighting the need for long-term follow-up.
In contrast to solitary MF, extracutaneous dissemination or disease-related death has never
been reported.1
Histopathologic features
Pagetoid reticulosis is characterized by epidermal hyperplasia with parakeratosis, prominent
acanthosis and florid epidermotropism of atypical lymphocytes typically scattered throughout
the epidermis1,20 (Fig. 4A). It is this pattern
of epidermotropism that is characteristic, and
despite the high number of intraepidermal
lymphocytes, Pautrier microabscesses are absent
or rare in the authors’ experience. The dermal
infiltrate in pagetoid reticulosis consists of reactive lymphocytes and histiocytes. In contrast, MF
is characterized by atypical lymphocytes above
and below the dermal-epidermal junction.38
In observing a pagetoid reticulosis pattern,
attention to clinical features is required to
4
Immunocytochemistry
In a recent review by Mourtzinos et al.45 the
neoplastic T-cells in pagetoid reticulosis were
CD8+/CD4− in 53% (Fig. 4C), CD4+/CD8−
in 36% and CD4−/CD8− in 11% of cases.
Furthermore, approximately 47% of pagetoid
reticulosis cases showed strong and extensive
CD30 expression; in such cases the distinction
from lymphomatoid papulosis is particularly
germane. High CD30 expression is uncommon
in patch stage MF, and is largely found in later
stages and/or large cell transformation.46 To
our knowledge, it has never been reported in
cases of solitary MF. The immunophenotype in
pagetoid reticulosis appears to be prognostically
irrelevant.45
T-cell receptor gene analysis
Previous studies have stated that the majority
of cases of pagetoid reticulosis reveal clonal
rearrangements on analysis of TCR genes.20,38,41
However, approximately 13 cases in which pagetoid reticulosis presented with a solitary lesion
were tested for clonality, and of those only 6 were
identified as clonal.31,38,47 – 49
Primary cutaneous CD4+ small/medium
pleomorphic T-cell lymphoma (SMPTCL)
SMPTCL has been credited to account for
approximately 3% of all primary cutaneous
lymphomas and is listed as a provisional entity
in the WHO-EORTC classification of cutaneous
lymphomas.1 With recent increased recognition, however, in the authors’ experience it is
probably the most common CTCL. To date,
many series of cases have been reported50 – 55
the largest of which included 133 patients with
solitary lesions.51 The relatively recently recognized entity of CD8+ lymphoid proliferation of
acral sites56 has been speculated to be a phenotypic variant of SMPTCL.57,58 It is a particularly
Review
A
B
C
Fig. 4. Pagetoid reticulosis is characterized by epidermal hyperplasia with parakeratosis, prominent acanthosis and florid
epidermotropism of atypical lymphocytes typically scattered throughout the epidermis (A, hematoxylin/eosin, ×100), similar to
that seen in lymphomatoid papulosis type D (B, hematoxylin/eosin, ×100). The neoplastic T-cells in pagetoid reticulosis are often
CD8+/CD4(−) (C, CD8 immunostain, ×100).
contentious neoplasm, both nosologically and
diagnostically.
Clinical features
SMPTCL usually presents with a solitary plaque
or tumor, on the face, neck or upper trunk1,51
(Fig. 5). In total, 231 solitary lesions of SMPTCL
have been described. Less commonly, it may
present with multiple lesions.50,52,53 SMPTCL
usually occurs in patients aged between 50 and
60 years old, although paediatric cases have
also been described.50,51,53 Cases presenting as
solitary skin lesions typically have an excellent
prognosis,50,51,53 although some cases have experienced recurrence of treated lesions50,51,53 – 55
or even extracutaneous spread and death52
(Table 1). The latter study describes five cases
in which there followed an aggressive clinical
course, all of whom had nodules >5 cm in size.
One of these cases co-expressed CD20, there
were technical problems with CD4 in another
and at least focal loss of CD4 was observed in
three, one of which transformed to large cell
lymphoma. However, no immunophenotyping for follicular helper T-cell expression was
performed and perhaps the diagnosis in these
Fig. 5. The typical clinical presentation of SMPTCL, consisting
of a solitary nodule on the left nose.
cases may be questioned. The WHO-EORTC
classification cites a 5-year survival of only
70% although subsequent reports – and most
authorities – now accept the prognosis is much
better.1 Baum et al.50 described waxing and
waning of lesions. The pathologic criteria for
diagnosis have evolved erratically rather than
been systematically defined, and framed within
5
Review
A
B
C
D
Fig. 6. SMPTCL presents with a dense dermal infiltrate consisting predominantly of small/medium pleomorphic Tcells, often with
hyperchromatic angulated nuclei, which exhibit a tendency to extend to the subcutis (A&B, hematoxylin/eosin, ×40 and ×100,
respectively). Rosettes of neoplastic T-cells are highlighted by PD-1 (C, PD-1, ×200) and a heavy B-cell population is oftentimes
present (D, CD20, ×40).
historical perspectives of ‘pleomorphic nodular’
lymphoma and, pseudo-T-cell lymphoma.
Histopathologic features
SMPTCL almost always presents a dense infiltrate of predominantly small/medium pleomorphic T-cells packing the dermis, with a tendency to extend to the subcutis. The cells have
hyperchromatic angulated nuclei (Figs. 6A,B). A
small proportion of large cells may be observed
(by definition, <30%).1 Epidermotropism may
be present focally54 and in some cases there
are a considerable number of small reactive
lymphocytes.
Immunocytochemistry
By definition, the phenotype in SMPTCL is
CD3+, CD4+, CD8−, CD30−.1 However, CD8+
variants have been described, some of which are
lacking detailed analysis.51 One CD8+ variant
was described to occur on the foot and appeared
to have an indolent clinical course.54 It is now
recognized that SMPTCL is a neoplasm of follicular T-helper cells and, accordingly, expresses
PD-1, ICOS, CXCL-13, bcl-6 and CD10 (Fig. 6C).
6
Interestingly, these markers are not consistently expressed to the same degree – perhaps
reflecting differing specificities, but also that
immunophenotype at extranodal sites does
not always mirror the nodal findings.59 A few
authors stress the finding of rosettes of neoplastic T-cells highlighted by the immunophenotype
(Fig. 6C) and often surrounding a B-cell infiltrate (Fig. 6D).55 The follicular T-helper cell
phenotype is believed to underlie the prominent B-cell population that is a consistent feature
of this tumor.53,55
Problems of definition and diagnosis
The usual difficulty when faced with this tumor
is deciding whether the dense but quite polymorphous infiltrate is reactive or neoplastic.
The concept of ‘nodular T-cell pseudolymphoma’ is a source of further obfuscation. In the
authors’ view, terms such as pseudolymphoma
(PSL) or nodular T-cell pseudolymphoma are
unhelpful and misleading.60 Many literature
reports attest to the varied conditions that can
mimic a lymphomatous infiltrate, including
drug ingestion, Jessner’s lymphocytic infiltrate,
arthropod reactions, lymphomatoid keratosis,
Review
A
B
C
Fig. 7. Indolent CD8-positive lymphoid proliferation most
commonly occurs on the ear (A), but it has also been reported
to involve the feet (B) or hands (C).
herpes infection, contact dermatitis, tattoo and
pseudolymphomatous folliculitis (PLF).60 – 64
Therefore, T-cell pseudolymphoma sui generis
does not exist; instead, the plethora of conditions reported should simply warn the wary
pathologist of mistaking a diagnosis for lymphoma in certain settings. In addition, no
consensus definition of ‘nodular T-cell pseudolymphoma’ has been reported to the authors’
knowledge. Most publications of this ‘entity’
date before the year 2000, and have not been
subject to modern techniques for assessing clonality or follicular T-helper cell phenotyping.60
One recent report did seek to compare PSL
with SMPTCL but included a PSL in the latter as
they were deemed to be ‘identical’, prejudging
the very comparison.65 In fact, any attempted
comparison between SMPTCL and ‘nodular
T-cell pseudolymphoma’ is problematic as they
are likely one and the same. If no causative
stimulus is identified for an infiltrate that has at
least some features suggestive of lymphoma to
the pathologist then, in our opinion, the diagnosis should be ‘lymphoid infiltrate of uncertain
nature’ rather than ‘T-cell pseudolymphoma’.
Since the demonstration of a follicular helper
T-cell phenotype, it is reasonable to insist this
is a required diagnostic criterion for SMPTCL,
although which are the more reliable markers of
this phenotype is not entirely clear. Our group
examined whether follicular helper T-cells were
present within the infiltrates of a broad range of
reactive dermatoses, including drug reactions.
In these cases, the expression of PD-1, ICOS and
CXCL-13 was always low, and lacked rosettes.66
Clonality is observed in around 60–70% of
cases but Grogg et al.53 assert that a dominant
T-cell clone should be an essential criterion.
Although, clonal rearrangements of the TCR
are highly suggestive of lymphoma, it is accepted
that reactive conditions may also exhibit T-cell
monoclonality,64 making it unsatisfactory to use
this as a definitive tool. In the authors’ view, the
typical microscopic features should be combined
with widespread expression of PD-1 exhibiting a
rosette pattern, and at least one more of either
bcl-6, ICOS, CXCL-13 or CD10; loss of a T-cell
antigen and/or T-cell clonality are additional
supportive features if present. We suggest that
in such cases, arising in the clinical context of
features typically as depicted in Fig. 5, it is more
than reasonable to assert a diagnosis of T-cell
lymphoma, albeit one which is almost certainly
low-grade.
The heavy B-cell population oftentimes
present (Fig. 6D) underlies a further common
diagnostic problem viz. a solitary lesion having
a mixed T- and B-cell infiltrate, with relatively
low-grade atypia, causes difficulties for pathologists in determining whether it is a T or B-cell
malignancy. Marginal zone lymphoma (MZL)
and T-cell rich B-cell lymphoma (TCRB) – each
often with heavy T-cell populations – enter the
differential diagnosis. Both are outside the scope
of this review but, with respect to MZL, attention
should be paid to plasmacytoid differentiation
and the presence of monoclonal population
with in-situ hybridization to light chains. TCRB
is not afforded a separate primary cutaneous
category in the WHO-EORTC classification, and
while convincing reports exist67 it is interesting
to postulate whether at least some reported
examples reflect confusion between variants of
MZL and SMPTCL.
Finally, since the observation of the follicular T-helper phenotype, several reports
have emerged of a putative entity, ‘follicular
T-helper cell lymphoma’ (FTHCL), and this
has included solitary and multiple forms.68 The
relationships between SMPTCL, FTHCL and
angioimmunoblastic lymphoma (AIL) – also a
helper T-cell neoplasm – remain to be elucidated but thus far it appears that solitary tumors,
as usually seen with SMPTCL, have an excellent
7
Review
A
B
C
D
Fig. 8. Indolent CD8-positive lymphoid proliferation exhibits a dense, diffuse, dermal lymphoid infiltrate with a Grenz zone (A&B,
hematoxylin/eosin, ×100). Rare cases with one or two Pautrier collections have been reported (C, hematoxylin/eosin, ×200) and
the infiltrate is characteristically monotonous (D, hematoxylin/eosin, ×100).
prognosis, while in the presence of multiple
lesions, as seen in FTHCL and AIL, predictions
should be more guarded. Such preliminary
findings should obviously be taken into account
while planning appropriate therapy.
T-cell receptor gene analysis
In one of the largest published series on
SMPTCL, monoclonal rearrangements of the
TCR were demonstrated in 60% of cases.51 Some
studies reported even higher proportions.53
Clinical features
Clinically, they present as erythematous papules
or nodules, often on the ears, but two have
occurred on the nose,70,71 and also hands and
feet (Figs. 7B,C). It appears to have a predilection for males, and has a mean incidence age
of 54 years.58 Lesion recurrence post-treatment
has been reported, but there is no evidence as
yet to suggest that this entity has an aggressive
nature.4,57,58,69 Nevertheless, at least one patient
continues to develop small papules at various
acral sites.69
Indolent CD8+ lymphoid proliferation of acral sites
To date, only 22 solitary lesions of indolent CD8+
lymphoid proliferation have been described. A
recent report described six patients with a wider
constellation of clinical sites and microscopic
features than previously recognized.69 Given
the occurrence on the foot and hands, it was
suggested that indolent CD8+ lymphoid proliferation of acral sites was a more apposite name,
although the ear remains the most common
location (Fig. 7A).
Histopathologic features
Indolent CD8+ lymphoid proliferation presents
with a dense, diffuse, dermal lymphoid infiltrate, separated from the epidermis by a zone
of sparing (Figs 8A,B). Foci of epidermotropism
and even an occasional Pautrier microabscess
have been reported (Fig. 8C), but follicular and
sweat apparatus involvement are never seen.69
The infiltrate consists of atypical medium-sized
lymphocytes with a small minority population
of reactive lymphocytes (mainly B-cells). The
8
Review
SOLITARY LESION
(nodule/papule/patch/plaque)
(Assumes careful clinical examination and staging is negative)
Epidermotropism and/or folliculotropism/syringotropism?
YES
No /minimal cytological
atypia/no abnormal ICC
/polyclonal?
Lining up#/Pautrier
collections?
NO
PR pattern/acral site/CD8+
phenotype?
Folliculitis*
Other e.g:
lymphomatous
drug reaction*
-significant cytological
atypia
-loss of T-cell antigens
-clonal
No Grenz zone, occasional
intraepidermal lymphocytes,
extends to subcutis?
Monomorphic
atypical cells
+ Any of:
‘REACTIVE’
Grenz zone ?
Pagetoid
Reticulosis
NO
YES
CD8+ phenotype
Solitary MF
Indolent CD8+
lymphoid proliferation
CD4+ PD-1+
phenotype/rosettes. Positive for
any of bcl-6, ICOS, CXCL-13
or CD10, Numerous B-cells,
loss of T-cell antigens, clonal.
Num
SMPTCL
Fig. 9. Diagnostic algorithm for solitary cutaneous T-cell lymphomas. MF, mycosis fungoides; PR, pagetoid reticulosis; ICC,
immunocytochemistry; SMPTCL, primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoma; * Further investigations
required to clarify disease or etiology; # of atypical lymphocytes.
lymphocytes are described as pleomorphic in
some cases,56 but monomorphic in most other
reports.4,58,69,70 The infiltrate is characteristically monotonous in the authors’ experience
(Fig. 8D) and differs from the more obviously
polytypic infiltrate of SMPTCL. All cases of
indolent CD8+ lymphoid proliferation have a
CD8+ phenotype, by definition. Beltraminelli
et al.56 has suggested that, based on morphology, indolent CD8+ lymphoid proliferation best
fits into the WHO/EORTC category of SMPTCL
and that it should be considered a phenotypic variant of SMPTCL. Swick et al.58 and
Kempf et al.57 agreed with this suggestion and
Geraud et al.72 described another case of this
entity and termed it ‘primary cutaneous CD8+
small/medium sized pleomorphic T-cell lymphoma, ear type’. However, a recent series by
Greenblatt et al.69 found a complete absence of
expression of follicular helper T-cell markers in
four cases, and the tumor cell morphology – in
most publications – seems quite distinct from
SMPTCL.
Locally directed therapy is the treatment
of choice. Wider recognition of this entity
is required to prevent unnecessarily aggressive chemotherapy for what is otherwise often
labelled Peripheral T-cell Lymphoma NOS,
a category usually interpreted as signifying
life-threatening disease.
Immunocytochemistry
By definition tumor cells express CD8, diffusely
and strongly in all cases so far, and might have
loss of expression of one or more T-cell associated antigens. In most examples, there is a low
proliferative fraction, and, although the neoplastic cells express TIA-1, they are usually granzyme
B and perforin negative. A few exceptions have
been recently documented with higher than
usual (30–40%) Ki-67 index and tumors positive
for granzyme B.69
T-cell receptor gene analysis
Of the 22 described cases of indolent CD8+
lymphoid proliferation, 14 were analyzed for
TCR rearrangements and 13 were found to be
clonal.4,56 – 58,71 – 73
Other lymphomas reported occurring as solitary
lesions
A wide variety of lymphomas have been reported
as presenting with a solitary lesion. These include
anaplastic CD30+ large cell lymphoma,74 which
commonly presents as a single tumor, but clearly
9
Review
spread from a systemic primary needs to be
excluded; lymphomatoid papulosis,75 although
such cases reflect the initial presentation, as
a single lesion is inevitably followed by crops
of papules; subcutaneous panniculitis-like T-cell
lymphoma,2 and CD20+ cutaneous T-cell lymphoma NOS.76 A repeated observation in the
majority of such cases is the excellent prognosis.
Recommendations
On the basis of the literature review presented
herein, we have proposed a system for the diagnosis of some of lymphomas that might present
as a solitary lesion, which involves clinical, microscopic, immunocytochemical and molecular
biologic features (Fig. 9). The proposed algorithm summarizes many of the points discussed.
Conclusion
A variety of cutaneous T-cell lymphomas can
present as a solitary lesion, and regardless of
type these almost always have a better clinical outcome than the more common multiple
counterpart; treatment can aim, therefore, to be
curative. Nevertheless, follow-up is warranted.
We propose a system to aid in the classification
of these lesions based on a combination of clinical, histopathologic, immunocytochemical and
molecular biologic features.
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11
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