J Cutan Pathol 2014 © 2014 John Wiley & Sons A/S. doi: 10.1111/cup.12353 Published by John Wiley & Sons Ltd John Wiley & Sons. Printed in Singapore Journal of Cutaneous Review A review of the solitary cutaneous T-cell

Cutaneous T-cell lymphomas (CTCL) account for almost 65-92% Mina S. Ally1 and Alistair of all cutaneous lymphomas, many of which usually present with Robson2 multiple lesions. However, a number of well-recognized and rare 1Department of , Stanford types of CTCL, including , can present in University School of , Redwood City, isolated fashion. These solitary lesions often run a relatively CA, USA, and indolent clinical course but often pose diagnostic difficulties. We 2St. John’s Institute of Dermatology, review histopathologically challenging solitary cutaneous T-cell St. Thomas’ Hospital, London, UK lymphomas, including criteria for diagnosis, clinical course and prognosis, particularly for primary cutaneous CD4+ small/medium pleomorphic 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, , indolent Alistair Robson, FRCPath Dip RCPath, CD8+ lymphoid proliferation of acral sites, primary cutaneous St. John’s Institute of Dermatology, St. Thomas’ CD4+ small/medium pleomorphic lymphoma Hospital, Westminster Bridge Road, London SE1 7EH, UK Ally MS, Robson A. A review of the solitary cutaneous T-cell Tel: 0207 1887188 Fax: +44 207 1886382 lymphomas. e-mail: [email protected] J Cutan Pathol 2014. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Accepted for publication December 16, 2013

Primary cutaneous T-cell lymphomas present run a relatively indolent clinical course, they in the skin with no evidence of extra-cutaneous continue to pose diagnostic difficulty. involvement.1 Cutaneous T-cell lymphomas In this review, we present an overview of the (CTCL) account for almost 65–92% of all cuta- solitary cutaneous T-cell lymphomas that, in neous lymphomas,2 of which, mycosis fungoides our opinion, present the greatest challenge in (MF) is the most common and characteristically diagnosis and that have been emerging over the presents with multiple lesions. However, solitary last 5 years. We have excluded some of the more MF, including and distinct from pagetoid retic- clinically aggressive tumors that may present as ulosis (Woringer-Kolopp), is well documented;3 solitary lesions as they tend to be well recognized similarly, other well-characterized forms of and histopathologically and immunopheno- lymphoma can present as an isolated lesion. typically distinct. We discuss the criteria for Finally, a number of increasingly recognized diagnosis, particularly for primary cutaneous rarer CTCL commonly present with an isolated CD4+ small/medium pleomorphic lymphoma lesion, including CD4+ small/medium pleomor- and indolent CD8+ lymphoid proliferation phic T-cell lymphoma (SMPTCL) and indolent of acral sites. Finally, we suggest an algorithm CD8+ lymphoid proliferation of acral sites.4 to aid in the diagnosis of such problematic Although it seems that these isolated lesions lesions.

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Cutaneous lymphoma classification and review single erythematous scaly patch or plaque, in non-sun-exposed areas.1 Solitary MF has been The recent détente and concord between 3,13,14 the World Health Organization (WHO) and reported to have an excellent prognosis, European Organization for the Research and although recurrence of treated lesions has been 2,13,15–18 Treatment of Cancer (EORTC) classifications reported six of which occurred distant acknowledges the unique features of primary from the site of the original lesion (Table 1). Two cutaneous lymphomas, which differ greatly from of these distant recurrences presented as multi- the nodal and other extranodal lymphomas.1,5 ple lesions, but in both cases, there was complete An accurate diagnosis of primary cutaneous resolution with further treatment and no further 2 lymphoma requires the correlation of the clini- disease at follow-up. The other four cases pre- 11,17 cal findings with the microscopic, immunophe- sented as a unilesional recurrence. In addi- notypic and genetic features. Given that the tion, four cases of solitary MF have progressed to further cutaneous involvement, three of which majority of lymphomas usually present with mul- , , , tiple lesions it is difficult to make a diagnosis had large cell transformation.2 8 16 19 of a specific cutaneous lymphoma when faced Solitary lesions of follicular and syringotropic with the clinical presentation of a solitary lesion. MF are also clinically and pathologically indis- Moreover, in the absence of multiple lesions the tinguishable from lesions seen in classical dis- surgical pathologist is frequently in difficulty in ease. Solitary folliculotropic MF presents as an determining whether an infiltrate is neoplastic infiltrated patch, plaque or an isolated areaof or reactive. follicular papules without prominent scaling, , , To date, of the solitary cutaneous T-cell usually in the head and neck area.2 6 8 Solitary lymphomas reported in the literature, approxi- syringotropic MF usually presents with a single mately 166 cases represent MF,3 231 represent erythematous, indurated plaque, often studded SMPTCL, 22 represent indolent CD8+ lym- with small pinhead-sized papules, in the trunk, , phoid proliferation and 62 represent pagetoid hip and thigh area,11 20 although cases have reticulosis (Table 1). been reported in the head and neck area.11,12 Alopecia is a prominent feature in both cases.11 Solitary MF There is still uncertainty about the relation- ship between these two MF subtypes, but they MF accounts for almost 50% of all primary cuta- often co-exist.6,11,20 When compared with clas- neous lymphomas and is characterized by mul- 1 sic MF, folliculotropic MF is typically associated tiple patches and plaques. Indeed, given that with a poorer prognosis.21 This is sometimes,8 the finding of multiple patches and plaques but not always the case for solitary lesions.2,6 is a defining feature it is somewhat contradic- Syringotropic MF, however, has a prognosis sim- tory to consider a solitary variant. Nevertheless, ilar to that of classic MF.22 Out of the nine soli- since 1981, 166 solitary cases of MF have been tary cases of syringotropic MF reported, one has described that are distinct from pagetoid retic- shown recurrence of the lesion distant from the ulosis, including 10 of the folliculotropic variant 11 , , original site. (follicular MF)2 3 6–8 and 9 cases of syringotropic Finally, the report of an EORTC workshop con- MF.9–12 cerning granulomatous MF and (GSS) detailed one solitary example Clinical features of GSS.23 Recently, at the senior author’s insti- Solitary MF, clinically and histopathologically tution, a case of GSS presented with a single resembles classic MF. Clinically, it presents as a 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 Cases with cutaneous/ Cases with lesion recurrence lymphoma type Total cases systemic progression post-treatment*

Solitary MF 166 4 (Cutaneous spread, 3 × large cell transformation) 15 (six distant from original site) Pagetoid reticulosis (Woringer-Kolopp) 62 1 (Cutaneous spread) 8 (1 distant from original site) SMPTCL 231 5 (Extracutaneous spread, one died of lymphoma) 12 Indolent CD8+ lymphoid proliferation of 22 0 4 (one distant from original site) acral sites

*Recurrence occurred at the same site of the original lesions unless stated otherwise.

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Fig. 2. ’Lining up’ of atypical lymphocytes at the dermoepider- mal junction and fibrotic changes in the papillary dermis are Fig. 1. A solitary plaque of granulomatous slack skin, affecting noted in a solitary patch of mycosis fungoides involving the the groin. thigh of a 75-year male (hematoxylin/eosin, ×100). several years later with involvement of the groin 24 3 loss of T-cell associated antigens, T-cell clonality (Fig. 1). A recent report by Ally et al. of 15 and appropriate clinical appearance. cases suggested that the observation of solitary MF might be expected, albeit exceptional, in Immunocytochemistry which the disease is simply found at an uncom- monly early stage. The unsurprising excellent Immunophenotypically, solitary MF, like classic prognosis of such cases indicates that MF, is usually a neoplasm of CD4+ T-helper shouldaimtobecurative. cells, although CD8+ and double negative CD4−/CD8− variants have been described.28 In addition, there may be variable antigen loss of Histopathologic features CD2, CD5 and CD7.3 These immunophenotypes In solitary MF, microscopic sections show a super- do not seem to affect prognosis.28,29 ficial lymphoid infiltrate of epidermotropic and atypical lymphocytes.20,25 Atypia is usually more pronounced in the epidermotropic lymphocytes T-cell receptor gene analysis than those in the dermis.26,27 Other histopatho- T-cell receptor (TCR) gene rearrangements are logic features include lining up of atypical detected in approximately 57–71% of cases of lymphocytes at the dermoepidermal junction, early MF,29 so solitary lesions might be expected Pautrier microabscesses and fibrotic changes in to have a similar or perhaps lower clonal preva- the papillary dermis, none of which is specific lence. Out of the 166 cases of solitary MF for the diagnosis of MF11 (Fig. 2). Indeed, Cer- published, approximately 76 were tested for roni et al.’s13 series of 20 cases lacked many of TCR clonality, of which 45 cases had a clonal , , , , , these features. Folliculotropic and syringotropic TCR rearrangement.3 13 16 20 28 30 –32 The detec- MF are characterized by infiltration of atypical tion of monoclonal TCR rearrangements does , , lymphocytes within and around the hair follicle not appear to be of prognostic impact.13 16 29 and/or eccrine epithelium6,8 sometimes with follicular mucinosis.20 However, atypia can be minimal and distinction from idiopathic prior Pagetoid reticulosis (Woringer-Kolopp) to follicular mucinosis is problematic; follow-up In 1939, Woringer and Kolopp reported a soli- with repeated biopsies may be required. Thus, tary plaque on the forearm of a 13-year-old in short, the histopathologic features of solitary boy, which resembled MF. Since then, the lesions of MF mimic the features of the classic term pagetoid reticulosis was introduced, to disease. recognize the similarity between the atypical In the context of a solitary lesion, perhaps the epidermotropic cells in this disease and the burden of proof for the diagnosis should be intraepidermal adenocarcinomatous cells of particularly stringent; in Ally et al.’s3 series of 15 Paget’s disease of the nipple.33 In the 2005, patients there were at least two of the following; WHO/EORTC classification of cutaneous lym- morphological and cytological features of MF, phomas, pagetoid reticulosis is classified as a

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distinguish these cases from (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, micro- scopic distinction of pagetoid reticulosis from some cases of CD8+ 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. Immunocytochemistry In a recent review by Mourtzinos et al.45 the neoplastic T-cells in pagetoid reticulosis were variant of MF, despite having distinct clinical 14,34–36 CD8+/CD4− in 53% (Fig. 4C), CD4+/CD8− and histopathologic features. in 36% and CD4−/CD8− in 11% of cases. Furthermore, approximately 47% of pagetoid Clinical features reticulosis cases showed strong and extensive The typical lesion of pagetoid reticulosis is a CD30 expression; in such cases the distinction solitary, slow growing, well circumscribed, psori- from lymphomatoid papulosis is particularly asiform or hyperkeratotic plaque1,20,37 (Fig. 3). germane. High CD30 expression is uncommon in patch stage MF, and is largely found in later In some cases, patients present with multiple 46 lesions.38 Pagetoid reticulosis typically affects stages and/or large cell transformation. To the distal extremities,33 although, lesions on our knowledge, it has never been reported in the trunk39 and even the tongue38 have been cases of solitary MF. The immunophenotype in pagetoid reticulosis appears to be prognostically described. Pagetoid reticulosis can affect any age 45 group including young children40 and usually irrelevant. has an indolent clinical course, although there is potential for dissemination and malignant T-cell receptor gene analysis behavior.20,41 Some cases have been associated Previous studies have stated that the majority with the development of MF several years after 38,42 of cases of pagetoid reticulosis reveal clonal the development of pagetoid reticulosis, , , rearrangements on analysis of TCR genes.20 38 41 highlighting the need for long-term follow-up. However, approximately 13 cases in which page- In contrast to solitary MF, extracutaneous dis- toid reticulosis presented with a solitary lesion semination or disease-related death has never were tested for clonality, and of those only 6 were been reported.1 identified as clonal.31,38,47 –49

Histopathologic features + Pagetoid reticulosis is characterized by epider- Primary cutaneous CD4 small/medium mal hyperplasia with parakeratosis, prominent pleomorphic T-cell lymphoma (SMPTCL) acanthosis and florid epidermotropism of atyp- SMPTCL has been credited to account for ical lymphocytes typically scattered throughout approximately 3% of all primary cutaneous the epidermis1,20 (Fig. 4A). It is this pattern lymphomas and is listed as a provisional entity of epidermotropism that is characteristic, and in the WHO-EORTC classification of cutaneous despite the high number of intraepidermal lymphomas.1 With recent increased recogni- lymphocytes, Pautrier microabscesses are absent tion, however, in the authors’ experience it is or rare in the authors’ experience. The dermal probably the most common CTCL. To date, infiltrate in pagetoid reticulosis consists of reac- many series of cases have been reported50–55 tive lymphocytes and histiocytes. In contrast, MF the largest of which included 133 patients with is characterized by atypical lymphocytes above solitary lesions.51 The relatively recently recog- and below the dermal-epidermal junction.38 nized entity of CD8+ lymphoid proliferation of In observing a pagetoid reticulosis pattern, acral sites56 has been speculated to be a pheno- attention to clinical features is required to typic variant of SMPTCL.57,58 It is a particularly

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AB

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 expe- 50,51,53–55 rienced recurrence of treated lesions Fig. 5. The typical clinical presentation of SMPTCL, consisting 52 or even extracutaneous spread and death of a solitary nodule on the left nose. (Table 1). The latter study describes five cases in which there followed an aggressive clinical course, all of whom had nodules >5cminsize. cases may be questioned. The WHO-EORTC One of these cases co-expressed CD20, there classification cites a 5-year survival of only were technical problems with CD4 in another 70% although subsequent reports – and most and at least focal loss of CD4 was observed in authorities – now accept the prognosis is much three, one of which transformed to large cell better.1 Baum et al.50 described waxing and lymphoma. However, no immunophenotyp- waning of lesions. The pathologic criteria for ing for follicular helper T-cell expression was diagnosis have evolved erratically rather than performed and perhaps the diagnosis in these been systematically defined, and framed within

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AB

CD

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’ Interestingly, these markers are not consis- lymphoma and, pseudo-T-cell lymphoma. tently expressed to the same degree – perhaps reflecting differing specificities, but also that Histopathologic features immunophenotype at extranodal sites does not always mirror the nodal findings.59 Afew SMPTCL almost always presents a dense infil- authors stress the finding of rosettes of neoplas- trate of predominantly small/medium pleomor- tic T-cells highlighted by the immunophenotype phic T-cells packing the dermis, with a ten- (Fig. 6C) and often surrounding a B-cell infil- dency to extend to the subcutis. The cells have trate (Fig. 6D).55 The follicular T-helper cell hyperchromatic angulated nuclei (Figs. 6A,B). A phenotype is believed to underlie the promi- small proportion of large cells may be observed nent B-cell population that is a consistent feature < 1 , (by definition, 30%). Epidermotropism may of this tumor.53 55 be present focally54 and in some cases there are a considerable number of small reactive Problems of definition and diagnosis lymphocytes. The usual difficulty when faced with this tumor is deciding whether the dense but quite poly- Immunocytochemistry morphous infiltrate is reactive or neoplastic. By definition, the phenotype in SMPTCL is The concept of ‘nodular T-cell pseudolym- CD3+,CD4+,CD8−,CD30−.1 However, CD8+ phoma’ is a source of further obfuscation. In the variants have been described, some of which are authors’ view, terms such as pseudolymphoma lacking detailed analysis.51 One CD8+ variant (PSL) or nodular T-cell pseudolymphoma are was described to occur on the foot and appeared unhelpful and misleading.60 Many literature to have an indolent clinical course.54 It is now reports attest to the varied conditions that can recognized that SMPTCL is a neoplasm of fol- mimic a lymphomatous infiltrate, including licular T-helper cells and, accordingly, expresses drug ingestion, Jessner’s lymphocytic infiltrate, PD-1, ICOS, CXCL-13, bcl-6 and CD10 (Fig. 6C). arthropod reactions, lymphomatoid keratosis,

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AB 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 C 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 Fig. 7. Indolent CD8-positive lymphoid proliferation most lymphoma, albeit one which is almost certainly commonly occurs on the ear (A), but it has also been reported low-grade. to involve the feet (B) or hands (C). The heavy B-cell population oftentimes present (Fig. 6D) underlies a further common herpes infection, contact dermatitis, tattoo and diagnostic problem viz. a solitary lesion having pseudolymphomatous folliculitis (PLF).60–64 a mixed T- and B-cell infiltrate, with relatively Therefore, T-cell pseudolymphoma sui generis low-grade atypia, causes difficulties for patholo- does not exist; instead, the plethora of con- gists in determining whether it is a T or B-cell ditions reported should simply warn the wary malignancy. Marginal zone lymphoma (MZL) pathologist of mistaking a diagnosis for lym- and T-cell rich B-cell lymphoma (TCRB) – each phoma in certain settings. In addition, no often with heavy T-cell populations – enter the consensus definition of ‘nodular T-cell pseu- differential diagnosis. Both are outside the scope dolymphoma’ has been reported to the authors’ of this review but, with respect to MZL, attention knowledge. Most publications of this ‘entity’ should be paid to plasmacytoid differentiation date before the year 2000, and have not been and the presence of monoclonal population subject to modern techniques for assessing clon- with in-situ hybridization to light chains. TCRB ality or follicular T-helper cell phenotyping.60 is not afforded a separate primary cutaneous One recent report did seek to compare PSL category in the WHO-EORTC classification, and with SMPTCL but included a PSL in the latter as while convincing reports exist67 it is interesting they were deemed to be ‘identical’, prejudging to postulate whether at least some reported the very comparison.65 In fact, any attempted examples reflect confusion between variants of comparison between SMPTCL and ‘nodular MZL and SMPTCL. T-cell pseudolymphoma’ is problematic as they Finally, since the observation of the fol- are likely one and the same. If no causative licular T-helper phenotype, several reports stimulus is identified for an infiltrate that has at have emerged of a putative entity, ‘follicular least some features suggestive of lymphoma to T-helper cell lymphoma’ (FTHCL), and this the pathologist then, in our opinion, the diag- has included solitary and multiple forms.68 The nosis should be ‘lymphoid infiltrate of uncertain relationships between SMPTCL, FTHCL and nature’ rather than ‘T-cell pseudolymphoma’. angioimmunoblastic lymphoma (AIL) – also a Since the demonstration of a follicular helper helper T-cell neoplasm – remain to be eluci- T-cell phenotype, it is reasonable to insist this dated but thus far it appears that solitary tumors, is a required diagnostic criterion for SMPTCL, as usually seen with SMPTCL, have an excellent

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AB

CD

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 Clinical features lesions, as seen in FTHCL and AIL, predictions Clinically, they present as erythematous papules should be more guarded. Such preliminary or nodules, often on the ears, but two have findings should obviously be taken into account occurred on the nose,70,71 and also hands and while planning appropriate therapy. feet (Figs. 7B,C). It appears to have a predilec- tion for males, and has a mean incidence age 58 T-cell receptor gene analysis of 54 years. Lesion recurrence post-treatment has been reported, but there is no evidence as In one of the largest published series on yet to suggest that this entity has an aggressive SMPTCL, monoclonal rearrangements of the , , , nature.4 57 58 69 Nevertheless, at least one patient TCR were demonstrated in 60% of cases.51 Some 53 continues to develop small papules at various studies reported even higher proportions. acral sites.69

Indolent CD8+ lymphoid proliferation of acral sites Histopathologic features To date, only 22 solitary lesions of indolent CD8+ Indolent CD8+ lymphoid proliferation presents lymphoid proliferation have been described. A with a dense, diffuse, dermal lymphoid infil- recent report described six patients with a wider trate, separated from the epidermis by a zone constellation of clinical sites and microscopic of sparing (Figs 8A,B). Foci of epidermotropism features than previously recognized.69 Given and even an occasional Pautrier microabscess the occurrence on the foot and hands, it was have been reported (Fig. 8C), but follicular and suggested that indolent CD8+ lymphoid prolifer- sweat apparatus involvement are never seen.69 ation of acral sites was a more apposite name, The infiltrate consists of atypical medium-sized although the ear remains the most common lymphocytes with a small minority population location (Fig. 7A). of reactive lymphocytes (mainly B-cells). The

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SOLITARY LESION (nodule/papule/patch/plaque) (Assumes careful clinical examination and staging is negative)

Epidermotropism and/or folliculotropism/syringotropism?

YES NO

No /minimal cytological Lining up#/Pautrier PR pattern/acral site/CD8+ Grenz zone ? No Grenz zone, occasional atypia/no abnormal ICC collections? phenotype? intraepidermal lymphocytes, /polyclonal? extends to subcutis?

+ Any of: Monomorphic atypical cells ‘REACTIVE’ -significant cytological Pagetoid atypia Reticulosis NO YES -loss of T-cell antigens -clonal CD4+ PD-1+ CD8+ phenotype phenotype/rosettes. Positive for Folliculitis* Other e.g: any of bcl-6, ICOS, CXCL-13 lymphomatous Solitary MF drug reaction* or CD10, Numerous B-cells, Indolent CD8+ loss of T-cell antigens, clonal. lymphoid proliferation

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 a category usually interpreted as signifying some cases,56 but monomorphic in most other life-threatening disease. reports.4,58,69,70 The infiltrate is characteristi- cally monotonous in the authors’ experience Immunocytochemistry (Fig. 8D) and differs from the more obviously polytypic infiltrate of SMPTCL. All cases of By definition tumor cells express CD8, diffusely and strongly in all cases so far, and might have indolent CD8+ lymphoid proliferation have a loss of expression of one or more T-cell associ- CD8+ phenotype, by definition. Beltraminelli 56 ated antigens. In most examples, there is a low et al. has suggested that, based on morphol- proliferative fraction, and, although the neoplas- ogy, indolent CD8+ lymphoid proliferation best tic cells express TIA-1, they are usually granzyme fits into the WHO/EORTC category of SMPTCL B and perforin negative. A few exceptions have and that it should be considered a pheno- been recently documented with higher than typic variant of SMPTCL. Swick et al.58 and usual (30–40%) Ki-67 index and tumors positive Kempf et al.57 agreed with this suggestion and for granzyme B.69 Geraud et al.72 described another case of this entity and termed it ‘primary cutaneous CD8+ T-cell receptor gene analysis small/medium sized pleomorphic T-cell lym- phoma, ear type’. However, a recent series by Of the 22 described cases of indolent CD8+ Greenblatt et al.69 found a complete absence of lymphoid proliferation, 14 were analyzed for TCR rearrangements and 13 were found to be expression of follicular helper T-cell markers in clonal.4,56–58,71–73 four cases, and the tumor cell morphology – in most publications – seems quite distinct from SMPTCL. Other lymphomas reported occurring as solitary Locally directed therapy is the treatment lesions of choice. Wider recognition of this entity A wide variety of lymphomas have been reported is required to prevent unnecessarily aggres- as presenting with a solitary lesion. These include sive chemotherapy for what is otherwise often anaplastic CD30+ large cell lymphoma,74 which labelled Peripheral T-cell Lymphoma NOS, commonly presents as a single tumor, but clearly

9 Review spread from a systemic primary needs to be biologic features (Fig. 9). The proposed algo- excluded; lymphomatoid papulosis,75 although rithm summarizes many of the points discussed. such cases reflect the initial presentation, as a single lesion is inevitably followed by crops of papules; subcutaneous panniculitis-like T-cell Conclusion lymphoma,2 and CD20+ cutaneous T-cell lym- A variety of cutaneous T-cell lymphomas can phoma NOS.76 A repeated observation in the present as a solitary lesion, and regardless of majority of such cases is the excellent prognosis. type these almost always have a better clini- cal outcome than the more common multiple counterpart; treatment can aim, therefore, to be Recommendations curative. Nevertheless, follow-up is warranted. On the basis of the literature review presented We propose a system to aid in the classification herein, we have proposed a system for the diag- of these lesions based on a combination of clin- nosis of some of lymphomas that might present ical, histopathologic, immunocytochemical and as a solitary lesion, which involves clinical, micro- molecular biologic features. scopic, immunocytochemical and molecular

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