Clinical manifestations and pathogenesis of cutaneous lymphomas: current status and future directions

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1 review Clinical manifestations and pathogenesis of cutaneous lymphomas: current status and future directions Belen Rubio-Gonzalez, 1 Jasmine Zain, 2 Steven T. Rosen 2 and Christiane Querfeld 1,2,3 1 Department of Pathology, City of Hope, 2 Department of Hematology/Hematopoietic Cell Transplantation, City of Hope, and 3 Division of Dermatology, City of Hope, Duarte, CA, USA Summary The primary cutaneous lymphomas are a heterogeneous group of T-, Natural Killer- and B- cell neoplasms with a wide range of clinical and pathological presentations, and with very different prognoses compared to systemic lymphomas. Recent studies have shown that the skin microenvironment, which is composed of various immune cell subsets as well as their spatial distribution and T-cell interactions through different chemokines and cytokines, has an important role in the development and pathogenesis of cutaneous lymphomas and has assisted in the development of novel and more effective immunotherapies. The following review will focus on the major subtypes of primary cutaneous lymphomas, including the clinical and histological patterns, molecular hallmarks, and current and future treatment strategies. Keywords: primary cutaneous lymphomas, tumour microenvironment, treatment strategies, immune checkpoints. The primary cutaneous lymphomas represent a heterogeneous group of T-, Natural Killer (NK)- and B- cell neoplasms. Primary cutaneous T-cell lymphomas (CTCL) account for approximately 70% of all primary cutaneous lymphomas with an annual age-adjusted incidence of cases per million people in the United States (Willemze et al, 2005; Talpur et al, 2012). Based on the revised World Health Organization and European Organization for Research and Treatment of Cancer (WHO-EORTC) classification (Willemze et al, 2005) mycosis fungoides (MF) and Sezary syndrome (SS) are the most common subtypes representing 53% of all cutaneous lymphomas, followed by CD30-positive lymphoproliferative disorders (LPDs): lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T-cell lymphoma (ALCL, Correspondence: Christiane Querfeld, Director, Cutaneous Lymphoma Program, Assistant Professor, Dermatopathology/ Dermatology, Department of Pathology, City of Hope, 1500 E. Duarte Road, Duarte, CA 91010, USA. cquerfeld@coh.org 30%), subcutaneous panniculitis-like T-cell lymphoma (SPTCL, 1%), peripheral T-cell lymphoma (PTCL) that includes three recognized entities (primary cutaneous CD4+ small/medium-sized pleomorphic T-cell LPD, primary cutaneous epidermotropic CD8+ T-cell lymphoma, and cutaneous gamma-delta T-cell lymphoma) and extranodal NK/T-cell lymphoma, nasal type (<1%) (Table I). There may be overlapping clinical features, making the diagnosis challenging. Primary cutaneous B-cell lymphomas (CBCL) represent 25 30% of all cutaneous lymphomas with an age-adjusted incidence rate of 39 per million people in the United States (Suarez et al, 2013). The WHO-EORTC classification for primary cutaneous lymphomas (Willemze et al, 2005) distinguishes the following three main subtypes of PCBCL: primary cutaneous follicle centre lymphoma (PCFCL) representing 55%, primary cutaneous marginal zone lymphoma (PCMZL) representing 35%, and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), accounting for 10% of all PCBCLs cases (Table I). Due to different treatment approaches, it is critical to differentiate PCBCL from systemic B-cell lymphomas with secondary skin involvement. An appropriate diagnostic workup of cutaneous lymphomas is important to establish the subtype, characterization of prognostic factors and making therapeutic decisions (Table II) (Querfeld et al, 2003; Olsen et al, 2007a; Kempf et al, 2012). The following review will focus on the major subtypes of primary cutaneous lymphomas, including the clinical and histological patterns, molecular hallmarks and treatment strategies. Mycosis fungoides and Sezary syndrome Clinical features Mycosis fungoides (MF) and SS are the prototypes of CTCL. Classic MF presents with erythematous patches and/or plaques that may evolve to tumours and/or erythroderma (Fig 1A, B, C). Initially, lesions have a propensity for photoprotected areas including the breasts, buttocks, lower trunk and groins. Three major subtypes of MF are recognized in the WHO- EORTC classification: folliculotropic MF (FMF), pagetoid reticulosis (PR) and granulomatous slack skin First published online 26 October 2016 doi: /bjh ª 2016 John Wiley & Sons Ltd

2 Table I. The revised World Health Organization/European Organization for Research and Treatment of Cancer consensus classification for primary cutaneous lymphomas with relative frequency and survival. Cutaneous T-cell and NK-cell lymphomas Frequency (%) 5-year survival (%) Indolent Mycosis fungoides MF variants and subtypes Folliculotropic MF Pagetoid reticulosis Granulomatous slack skin Primary cutaneous CD30+ lymphoproliferative disorders Lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma 1 82 Primary cutaneous CD4+ small/medium-sized pleomorphic 2 72 T-cell lymphoproliferative disorder (provisional) Aggressive Sezary syndrome 3 24 Extranodal NK/T-cell lymphoma, nasal type <1 Primary cutaneous peripheral T-cell lymphoma, unspecified <1 18 Primary cutaneous epidermotropic CD8+ T-cell lymphoma (provisional) <1 Cutaneous c/d T-cell lymphoma (provisional) Cutaneous B-cell lymphomas Indolent clinical behaviour Primary cutaneous marginal zone lymphoma 7 99 Primary cutaneous follicular lymphoma Primary cutaneous diffuse large B-cell lymphoma, leg type 4 55 Primary cutaneous diffuse large B-cell lymphoma, other <1 50 Intravascular large B-cell lymphoma <1 65 Precursor hematologic neoplasm CD4+/CD56+ blastic plasmacytoid dendritic cell neoplasm 4 <1 < NK, natural killer. syndrome (GSS) (Willemze et al, 2005). However MF has numerous manifestations, posing a diagnostic challenge to the clinician and the pathologist. Early stage MF can mimic eczema or other inflammatory dermatoses. FMF often involves the head and neck area and upper torso (Fig 2A), with characteristic eyebrow involvement by patches/plaques and associated alopecia. Other findings are comedones, pustules, cysts, milia and prurigo nodularis-like lesions with alopecia. Patients with FMF have significant pruritus and a worse prognosis compared to classic MF (Cho-Vega et al, 2010). Pagetoid Reticulosis (Woringer-Kolopp disease) is an indolent MF variant that presents with a solitary, slowly progressing, hyperkeratotic plaque on acral areas (Fig 2B). The hypopigmented variant is seen in young patients and/or dark-skinned individuals (Fig 2C). The development of circumscribed erythematous pendulous patches and plaques on axillary and inguinal folds is characteristic of GSS (Fig 2D). This uncommon MF variant requires close monitoring because GSS has been associated with secondary neoplasias, especially Hodgkin lymphoma (Willemze et al, 2005; Kempf et al, 2008). Findings associated with disease progression in MF include the presence of large cell transformation (LCT) typically seen in patients with newly-developed cutaneous tumours (Fig 3A). Whereas MF is considered to have an indolent behaviour, SS is characterized by an aggressive course and presents with erythroderma and circulating malignant T lymphocytes ( cells/l) (Fig 4A, B, C), with or without peripheral lymphadenopathy (Vonderheid et al, 2002). Erythrodermic MF is distinguished from SS by low or absent circulating tumour cells. Morphological and immunophenotypic findings Patch/plaque lesions of MF show various degrees of epidermotropism consisting of single or clusters of atypical lymphocytes (Pautrier microabscess) and/or a superficial band-like infiltrate in the basal layer and superficial dermis, composed of small and medium-sized atypical T cells with irregular, hyperchromatic and cerebriform nuclei (Fig 1D). Tumour lesions of MF show deep dermal infiltrates, usually ª 2016 John Wiley & Sons Ltd 17

3 Table II. Recommended initial staging and work up for patients with CTCL and CBCL neoplasms. CTCL Complete physical examination Percentage of BSA involved of each type of skin lesion (patches, plaques, tumours,erythroderma, and/or any ulcerated, crusted/oozing lesion) mswat (MF/SS) Identification of any palpable lymph node ( 15 cm) or organomegaly Skin biopsy Immunostains for CD3, CD4, CD5, CD7, CD8, and one B-cell marker such as CD20. CD30 in large cell transformed MF, or if LyP, pcalcl is considered T cell receptor rearrangement analysis Laboratory work up CBC with differential, chemistry panel with LDH T cell receptor rearrangement analysis (compare to skin if positive) Flow cytometry for circulating Sezary cells (CD4+CD7 or CD4+CD26 ) (erythrodermic patients) HTLV-I/II titres in selected patients Imaging studies No imaging studies are required for stage IA/IB (T1N0M0B0; T2N0M0B0) CT scans of chest, abdomen, and pelvis (disseminated stage IB and higher) Combined PET/CT scans are recommended Lymph node biopsy Excisional biopsy for lymph nodes 15 cm and/or firm, irregular, clustered, or fixed nodes Biopsy of the largest lymph node draining an involved area or the node with highest standardized uptake value on PET/CT scans CBCL Complete physical examination Number of skin lesions, type (nodules, papules, plaques) and location Identification of any palpable lymph node ( 15 cm) or organomegaly Skin biopsy Immunostains for CD20, CD79a, CD3, CD5, CD10, BCL2, BCL6, Ki-67, kappa/lambda light chains In some cases: Cyclin D, surface IgM and IgD IGH or IGK gene rearrangements Cytogenetics or FISH t(14;18) in PCFCL Laboratory work up CBC with differential, chemistry panel with LDH, Borrelia burgdorferi, helicobacter pylori and ANA antibodies, RPR, viral hepatitis serologies Protein electrophoresis and quantitative Igs IGH/IGK rearrangement analysis (compare to skin if positive) Peripheral blood flow cytometry (if lymphocytosis. All PCDLBCL-LT cases) Bone marrow biopsy (disseminated skin disease, lymphadenopathy, all PCDLBCL-LT) Imaging studies Body CT scan with contrast in all patients Combined PET/CT scans are preferred Lymph node biopsy Excisional biopsy for lymph nodes 15 cm and/or firm, irregular, clustered, or fixed nodes Biopsy of lymph nodes with high PET activity Multidisciplinary assessment by dermatologists, oncologists, pathologists and social worker is highly recommended CTCL, primary cutaneous T-cell lymphomas; CBCL, primary cutaneous B-cell lymphomas; CBC, complete blood cell count; LDH, lactate dehydrogenase; HTLV-I/II, human lymphotropic virus I/II; BSA, body surface area; mswat, modified severity weighted assessment tool; MF, mycosis fungoides; SS, Sezary syndrome; LyP, lymphomatoid papulosis; pcalcl, primary cutaneous anaplastic large cell lymphoma; ANA, antinuclear antibodies; RPR, rapid plasma reagin; FISH, fluorescence in situ hybridization; Ig, immunoglobulin; PCDLBCL-LT, primary cutaneous diffuse large B-cell lymphoma, leg type; CT, computed tomography; PRT, positron emission tomography. with absent or diminished epidermotropism. The neoplastic T-cells are CD4+ and CD8 (Fig 1E, F), with frequent loss of CD5 and/or CD7. A CD8+ phenotype is characteristic of hypopigmented MF. Large cell transformation is defined by the presence of more than 25% of large lymphoid cells of the total cell infiltrate (Fig 3B). The large cells may express CD30 and cytotoxic markers and mimic ALCL or LyP. Histopathological features of erythrodermic MF and SS are often subtle or non-diagnostic. Peripheral blood flow cytometry can determine the absolute count of Sezary cells or circulating MF cells, which exhibit a CD4+ CD26 or CD4+ CD7 phenotypes (Olsen et al, 2007a). 18 ª 2016 John Wiley & Sons Ltd

4 (A) (B) (C) (D) (E) (F) Fig 1. Patients with classic mycosis fungoides. Disseminated patches (A), plaques (B), and tumours (C). Epidermotropism of atypical lymphocytes with Pautrier collections are seen (D). The atypical cells are positive for CD4 (E) and negative for CD8 (F). Panels D, E, F: Original magnification 920. (A) (B) (D) (C) Fig 2. Clinical variants of mycosis fungoides. Folliculotropic mycosis fungoides involving commonly head and neck areas (A). Pagetoid reticulosis presenting as hyperkeratotic large plaque on the right forearm (B). Hypopigmented mycosis fungoides involving the lower extremities (C), Granulomatous slack skin syndrome presenting as lax skin folds (D). Immunological and molecular hallmarks The skin-homing malignant lymphocytes in MF and SS typically show a mature CD4+ memory T-cell phenotype and can display differentiation markers of FOXP3 regulatory T cell (Treg) and T-helper cells type 2 or 17 (Th2 or Th17) cells (Dummer et al, 1996; Berger et al, 2005; Krejsgaard et al, 2011). Treg cells produce interleukin (IL)10 and transforming growth factor b (TGFb) which promote an immunosuppressive microenvironment in MF (Pandiyan & Zhu, 2015). Patch/plaque lesions (early stage MF) have a Th1 ª 2016 John Wiley & Sons Ltd 19

5 (A) (B) Fig 3. Mycosis fungoides with large cell transformation. Erythematous plaques and tumours on the right lateral leg (A). Mycosis fungoides morphology composed of large atypical lymphocytes (B, original magnification 920). (A) (B) (C) Fig 4. Patient with Sezary syndrome. (A) Erythroderma, (B) Palmoplantar keratoderma with superimposed infection, (C) Typical morphology of a circulating Sezary cell showing a hyperchromatic and hyperconvoluted nucleus. Original magnification cytokine profile with high expression of IL2, IL12 and c-interferon (INF-c), whereas in advanced-tumour stage MF, the immune milieu changes from a Th1 to Th2-cytokine profile. The Th2 cytokines (IL4, IL5, IL10 and IL13) may lead to peripheral eosinophilia and high serum levels of immunoglobulin (IgE), erythroderma, immunosuppression and increased susceptibility to bacterial infections that are major causes of death in advanced MF/SS. In contrast to Th1 and Th2 phenotypes, the Th17 phenotype has been observed in all stages of MF. Th17 cells are characterized by the production of proinflammatory IL17, which indirectly promotes tumour growth in CTCL, and its expression is promoted by the Jak3/Stat3 pathway (Krejsgaard et al, 2011). The migration of malignant T-cells to the skin is driven by the expression of various chemokine receptors and adhesion molecules involved in normal skin immunosurveillance. The expression of skin homing CCR4 facilitates migration into epidermis and dermis (Reiss et al, 2001; Ferenczi et al, 2002). The profile of chemokine receptors changes with disease progression and an increased expression of lymph node homing CCR7 is seen in tumour stage MF and SS. CCR7 expression has been correlated with loss of epidermotropism and promotes extracutaneous spread with the migration of T cells to the blood, secondary lymphoid organs and other organs (Kallinich et al, 2003; Sokolowska-Wojdylo et al, 2005). The malignant T cells of SS have a central memory T cell phenotype and are capable of circulating between skin, blood and lymph nodes; whereas those in MF are non-recirculating skin resident effector memory T cells (Campbell et al, 2010; Clark et al, 2012). These findings support the notion of MF and SS as two different diseases with distinct clinical behaviours. Chemokines produced by epidermal and dermal dendritic cells within the tumour microenvironment may also play important roles in attracting malignant T-cell to the skin and several studies have shown a protumourigenic role of mast cells and macrophages. Therefore the malignant T-cells might be functionally exhausted due to continuous antigen overload expressing PD1, LAG3, CTLA4 and ICOS similar to that seen in chronic viral infections suggesting a role for immune checkpoint inhibitor therapies (Querfeld et al, 2014; Rubio Gonzalez et al, 2016). Recent discoveries indicate that the oncogenic microrna MIR155 is overexpressed in affected skin from CTCL patients, and its expression is mediated by the Jak/Stat 5 pathway (Ralfkiaer et al, 2011). In mouse models, knockdown of Stat5 results in a 40% inhibition of MIR155 expression, supporting the use of MIR155 and JAK/STAT inhibitors as future therapeutic targets for relapsed/refractory CTCL (Kopp et al, 2013; Rubio Gonzalez et al, 2016). 20 ª 2016 John Wiley & Sons Ltd

6 Malignant T cells in MF and SS overexpress IL2RA (CD25) that results from a cascade of phosphorylation of several proteins including JAK3, STAT5 and STAT3 (Nielsen et al, 1999; Sommer et al, 2004). Genomic analysis studies have detected recurrent gain-of-function mutations targeting JAK1, JAK3, STAT3 and STAT5B in 11% of SS genomes, which suggest a role for JAK/STAT inhibitors for the treatment of CTCL. These studies also identified loss-of-function aberrations targeting members of the chromatin remodelling, such as ARID1A, as well as potential driver genes in SS, including POT1, TP53 and DNMT3A (Kiel et al, 2015; Woollard et al, 2016). Dysfunctional apoptosis due to decreased and/or defective apoptosis stimulating fragment (Fas) death receptor expression in neoplastic T cells has been associated with advanced disease and was recognized as an immune escape mechanism in CTCL. Multiple abnormalities including FAS gene mutations, promoter hypermethylation and the production of non-functioning splice variants have been observed, leading to apoptosis resistance and enabling continued neoplastic T-cell proliferation (Dereure et al, 2000; Wu et al, 2009a). Other cytogenetic aberrancies that have been recently found by whole-genomic sequencing in MF/SS samples are involved in the NF-kb signalling pathway. One of the latest discoveries is a recurrent CD152 CD28 fusion with large deletion of chromosome 2 that appears to transmit powerful co-stimulatory signals to neoplastic T-cells to enhance proliferation (Ungewickell et al, 2015). Prognosis and treatment options The prognosis of the disease depends on the type and extent of the skin lesions and extracutaneous involvement and is based on EORTC-International Society for Cutaneous Lymphoma (ISCL) recommendations (Lamberg & Bunn, 1979; Olsen et al, 2007a). Treatment strategies for MF/SS are determined by the extent of skin disease/ tumour burden, presence of unfavourable prognostic factors (folliculotropic type, large cell transformation and elevated lactate dehydrogenase and/or b2 microglobulin levels), age and other comorbidities that impact on the quality of life (Fig 5). Early stage MF (stages IA-IIA) has a favourable prognosis and skin-directed therapies including topical steroids, topical retinoids/rexinoids, psoralen combined with ultraviolet A (PUVA) or narrowband-uvb phototherapy, topical nitrogen mustard, spot radiation and total skin electron beam are first-line regimens (Table III) (Horwitz et al, 2008; Thomas et al, 2013; Zelenetz et al, 2016). In advanced stage MF/SS (stages IIB-IVB), treatment is aimed at reducing the tumour burden, which is usually estimated using the modified severity-weighted assessment tool (mswat), delaying disease progression and preserving quality of life (Table IV) (Querfeld et al, 2003, 2004; Olsen et al, 2007a,b; Wu et al, 2009b; Dummer et al, 2012; Jawed et al, 2014). Biological agents, such as a-interferon (IFN-a), retinoids (all-trans retinoic acid, isotretinoin), rexinoids (bexarotene) and low-dose methotrexate are commonly used as first-line monotherapy in advanced MF. These treatments are also used in combination with skin-directed regimens in patients with recalcitrant early stage disease (Zelenetz et al, 2016). Combination therapies with systemic retinoids and IFN-a do not appear to offer a higher response than IFN-a alone (Olsen, 2003) and appear inferior to IFN-a plus PUVA (Stadler & Otte, 1995). Extracorporeal photopheresis is effective in erythrodermic MF/SS, and bexarotene or IFN-a may enhance efficacy (Dippel et al, 1997; Haley et al, 1999). Methotrexate stimulates FAS pathway-induced apoptosis in MF, at least in part, by decreasing FAS/FASL promoter methylation and is particularly useful in patients with transformed MF (Wu et al, 2009a). Some studies suggest that the transformation at the time of the initial diagnosis may carry a better prognosis than LCT diagnosed later in the disease course (Benner et al, 2012), and does not require a different stage-based treatment compared to classic MF with similar stage. Spot radiation therapy is considered in cases with unifocal transformation or isolated/localized cutaneous tumours. Brentuximab vedotin is often effective in patients with multiple/disseminated CD30-positive tumours with LCT histology. Brentuximab vedotin is an antibody drug conjugate that selectively delivers a toxic microtubule-disrupting agent, monomethyl auristatin E, into CD30-expressing cells, inducing cell cycle arrest and apoptosis. This drug shows overall response rates of 70% in refractory or advanced MF or SS over a wide range of CD30 expression levels (Kim et al, 2015b). The most common adverse effects include peripheral neuropathy, fatigue, nausea, alopecia and neutropenia. Based on two large phase II studies, the US Food and Drug Administration (FDA) approved the intravenous histone deacetylase inhibitor (HDAC) romidepsin for relapsed/ refractory MF/SS (Piekarz et al, 2009; Whittaker et al, 2010). Romidepsin induced prolonged clinical responses, particularly in SS and MF patients with nodal or blood involvement, with manageable side-effects. Other HDAC inhibitors, vorinostat and panobinostat have shown similar activity (Duvic et al, 2009, 2013). A better understanding of the tumour microenvironment has assisted the development of novel and more effective immunotherapeutic strategies for relapsed/refractory CTCL, including IL2R-directed protein toxins, such as denileukin diftitox, anti-pd1/ anti-pdl1 agents, Toll-like receptor agonists, protein kinase C inhibitors, the phosphoinositide 3-kinase delta and gamma inhibitor Duvesilib, as well as the defucosylated humanized anti-ccr4 antibody mogalizumab (Horwitz et al, 2014; Jawed et al, 2014; Ogura et al, 2014; Balakrishnan et al, 2015). Unlike benign skin diseases, skin biopsies from CTCL patients have shown upregulation of MIR155, whereas MIR203 and MIR205 are repressed (Ralfkiaer et al, 2011). Currently, the efficacy of intralesional anti- MIR155 antibody for early stage MF is being evaluated in a phase-1 national clinical trial (NCT ) and results will be published next year. ª 2016 John Wiley & Sons Ltd 21

7 Fig 5. Stage-based treatment algorithm for mycosis fungoides and Sezary syndrome. ECP, extracorporeal photopheresis, HDACi, histone deacetylase inhibitor; IFN-a, alpha-interferon, NB-UVB, narrowband-ultraviolet light B; PUVA, psoralen ultraviolet light A; TSEBT, total skin electron beam therapy; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone Table III. Summary of treatments and response for patients with early stage mycosis fungoides (stage IA-IIA). Stage Therapy type Treatment Response Early stage MF (IA-IIA) Topical/skin directed therapy Steroids Phototherapy Nitrogen mustard Bexarotene Local radiation TSEBT ORR 80 90%; CRR 63%(T1), 25%(T2) CRR % (hypopigmented MF) CRR 76 80% stage IA, CRR 35 68% stage IB ORR 63%, CRR 21% CRR > 90%, low-dose (7 8 Gy) single or two fractions CRR 75% (T2), CRR 47% (T3) Refractory early stage MF (IA-IIA) Combination therapy PUVA or NBUVB and IFN-a (low-dose) PUVA or NBUVB and Bexarotene (low-dose) CRR 70% CRR 50 80% TSEBT, total skin electron beam therapy; PUVA, psoralen plus ultraviolet A light phototherapy; NBUVB, narrowband ultraviolet B light; IFN-a, interferon-alfa; ORR, overall response rate; CRR, complete response rate; MF, mycosis fungoides. 22 ª 2016 John Wiley & Sons Ltd

8 Table IV. Summary of treatments and responses for patients with advanced stage mycosis fungoides/ Sezary syndrome (stage IIB IVB). Therapy type Treatment Response Skin-directed therapy Immunomodulators Biologic/targeted therapies Combined therapy Systemic chemotherapy (Single-agent) Multiagent chemotherapy Stem cell transplant Investigational therapy TSEBT Interferons (IFN-a and IFN-c T) Retinoid/rexinoid (bexarotene) ECP Alemtuzumab HDACis (Romidepsin and Vorinostat) Antifolates (methotrexate, pralatrexate) IFN-a and phototherapy IFN-a and retinoids/rexinoids Retinoid and phototherapy ECP and INF-a ECP and retinoids/rexinoids Pegylated doxorubicin Purine/pyrimidine analogues (gemcitabine) CHOP/CHOP-like Autologous Allogenic Lenalidomide Bortezomib Brentuximab vedotin (anti-cd30) Anti-CCR4 antibody Anti-PD1/anti-PD-L1 antibodies TLR agonists Interleukin2 PI3-kinase d/c inhibitor (phase I trial) CRR 35% (10 20 Gy) ORR 29 80%; CRR 4 41% ORR 45 55% ORR 35 71%, CRR 14 26% ORR % (erythrodermic MF/SS) ORR 36% (Romidepsin), ORR 24% (Vorinostat) ORR 33 58% (methotrexate, low-dose), ORR 45% (pralatrexate, relapse/ refractory CTCL) CRR 70% CRR 50 80% CRR 38% CRR 44% No data available ORR % ORR 68 75% Comparable efficacy than single agents, higher toxicity CRR 83%, all relapse within median of 6 months ORR 68%, CRR 58% ORR 29% ORR 67% (relapsed/refractory CTCL) ORR 70% ORR 56% No data available ORR 32% ORR 18% ORR 27% TSEBT, total skin electron beam therapy; IFN-a, alpha-interferon; IFN-c, gamma-interferon; ECP, extracorporeal photopheresis; HDACis, histone deacetylase inhibitors; ORR, overall response rate; CRR, complete response rate; MF, mycosis fungoides; SS, Sezary syndrome; CTCL, cutaneous T cell lymphoma; PI3K -d/c inhibitor, phosphoinositide-3-kinase-delta/gamma inhibitor; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; TLR, Toll-like receptor. Primary cutaneous CD30+ lymphoproliferative disorders Clinical features Lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (PCALCL) are classified within the spectrum of primary cutaneous CD30+ lymphoproliferative disorders, with borderline cases that have overlapping characteristics. Primary cutaneous anaplastic large T-cell lymphoma frequently presents in male adults with solitary or localized tumours or nodules that do not spontaneous resolve and show ulceration (Fig 6A, B). Extracutaneous dissemination is observed in 10% of the patients and mainly involves the regional lymph nodes. Lymphomatoid papulosis generally occurs in younger adults, but may occur in children as well, and is characterized by multiple self-healing papules with overlying necrosis and recurrence over years (Fig 7A). Long-term follow-up is recommended as up to 20% of LyP patients are at risk of associated lymphomas, mainly MF, ALCL or Hodgkin lymphoma (Willemze et al, 2005; Wieser et al, 2015). Histopathology PCALCL is characterized by sheets of nonepidermotropic, large CD30+ atypical cells in the dermis with a background of reactive inflammation (Fig 6C, D). In 95% of cases, the neoplastic T-cells are CD4+ and CD30 must be expressed on more than 75% of the cells. Most PCALCL cases express the cutaneous lymphoma lymphocyte antigen (CLA) but do not express epithelial membrane antigen (EMA) and anaplastic lymphoma kinase (ALK), which are characteristically found in systemic ALCL. Lymphomatoid papulosis has heterogeneous histological presentations. Type A has a wedge-shaped dermal infiltrate of CD30+ large atypical lymphocytes, sometimes multinucleated or Reed-Sternberg-like, with numerous inflammatory cells (Fig 7B). Type B mimics mycosis fungoides with significant epidermotropism of atypical T-cells with cerebriform ª 2016 John Wiley & Sons Ltd 23

9 (A) (C) (B) (D) Fig 6. Patient with primary cutaneous anaplastic large T-cell lymphoma presenting as a solitary nodule (A) and cluster of tumour nodules involving genital area and inguinal folds (B). Sheets of large lymphoid cells in the dermis with a background of reactive inflammation (C), the atypical cells are positive for CD30 (D). Panels C, D: Original magnification 940 (A) (B) Fig 7. Patient with lymphomatoid papulosis (LyP) presenting with clustered small papules on the right antecubital fold (A). Pathology features of type A LyP: A wedge-shaped dermal infiltrate of large atypical lymphocytes, multinucleated or Reed-Sternberg-like cells and inflammatory cells, such as neutrophils (B, original magnification 940. nuclei. Type C may be difficult to distinguish from PCALCL, with sheets of large anaplastic cells with only few admixed inflammatory cells. Type D includes LyP cases with a CD8+ phenotype, and Type E has angiocentric and angiodestructive patterns. Distinguishing PCALCL and LyP can be challenging and often requires clinical observation to render a final diagnosis. Prognosis and treatment options Lymphomatoid papulosis and PCALCL have an excellent prognosis with 5-year disease-specific survivals of 100% and 95%, respectively. Patients with PCALCL who present with multifocal skin lesions with or without regional nodal involvement have a prognosis similar to patients with single or localized skin lesions only. Given that a curative therapy is not available for LyP and risk of disease progression is low, the short-term benefits of active treatment should be assessed against the potential side effects. In cases with few and non-scarring skin lesions, long-term follow up with observation, as well as topical steroids, should be considered. In cases that manifest with numerous papules or nodules and/or common recurrence, low-dose methotrexate (5-20 mg/week) is the most effective therapy, but the disease often relapses after discontinuation of treatment. Beneficial therapeutic effects have also been reported with PUVA and topical nitrogen mustard (Table V) (Kempf et al, 2011; Duvic et al, 2015; Gentile et al, 2015; Wieser et al, 2015). In PCALCL, radiotherapy or surgical excision are the firstline treatments for patients with solitary or localized skin 24 ª 2016 John Wiley & Sons Ltd

10 Table V. Summary of treatments and response for patients with primary cutaneous T-cell lymphoma other that MF and SS. CTCL subtype Treatment Response Primary cutaneous CD30+ lymphoproliferative disorder Lymphomatoid papulosis Limited skin disease Observation Class I High-potency topical steroids Intralesional corticosteroids Topical NM Bexarotene gel 1% Local Radiation CRR 12%, PRR 88% CRR 182%, PRR 409% CRR 26%, PRR 333% CRR 69% Disseminated skin disease and/or common recurrences Primary cutaneous anaplastic large T-cell lymphoma Solitary and/or localized disease PUVA Methotrexate (5 30 mg po weekly) Brentuximab vedotin Surgery Local RT CRR 26%, PRR 68% CRR 34%, PRR 66% CRR 75%, ORR 100% Multifocal skin disease Methotrexate (5 30 mg po weekly) Isolated cases with CR Extracutaneous involvement PTCL, indolent behaviour Primary cutaneous CD4+ small/medium- T-cell lymphoproliferative disorder Doxorubicin-based chemotherapy Brentuximab vedotin Observation Intralesional corticosteroids Surgical excision Low-dose radiation CRR 90% CRR 75%, ORR 100% Indolent CD8+ lymphoid proliferation of acral sites PTCL, aggressive behaviour Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma Intralesional corticosteroids Surgical excision Low-dose radiation Multiagent chemotherapy Allogeneic stem cell transplant Brentuximab for CD30+ cases Unsatisfactory results Isolated cases with CR Cutaneous gamma-delta T-cell lymphoma Subcutaneous panniculitis-like T cell lymphoma Extranodal NK/T-cell lymphoma Multiagent chemotherapy Allogeneic stem cell transplant Brentuximab vedotin for CD30+ cases Localized RT (solitary/localized disease) Oral bexarotene Clinical trials Methotrexate oral corticosteroids Localized RT (single/localized disease) Oral bexarotene Chemotherapy (SMILE-like regimen) Clinical trials CRR 21% CRR 57% ORR 75%(relapse/refractory) Isolated cases with CR ORR 82%, CRR 545% ORR 59%; CRR 33% ORR, overall response rate; CRR, complete response rate; PRR, partial response rate; CR, complete response; PTCL, peripheral T-cell lymphoma; RT, radiation therapy; NK, Natural Killer; NM, nitrogen mustard; PUVA, psoralen plus ultraviolet A light phototherapy; SMILE, dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide. ª 2016 John Wiley & Sons Ltd 25

11 lesions. In cases of disseminated/multifocal disease, low-dose methotrexate is usually recommended, and doxorubicinbased multiagent chemotherapy is used in rare cases with extracutaneous involvement or rapidly progressing tumours (Table V) (Kempf et al, 2011; Gentile et al, 2015). Brentuximab vedotin is the best systemic therapy based on the high expression of CD30 on the neoplastic cells (Duvic et al, 2015). Primary cutaneous peripheral T cell lymphoma, not otherwise specified (PTCL, NOS) PTCL represents a heterogeneous group of tumours that includes provisional entities with an aggressive clinical behaviour, such as primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma and primary cutaneous gamma-delta T-cell lymphoma, whereas others are characterized by an indolent course, such as primary cutaneous CD4+ small/ medium-sized pleomorphic T-cell lymphoma, and the indolent CD8-positive lymphoid proliferation of acral sites that is not currently recognized in the WHO/EORTC classification of primary cutaneous lymphomas (Table I) (Willemze et al, 2005). For the remaining diseases that do not fit into these provisional categories, the designation of PTCL, NOS is used (Fig 8C). Primary cutaneous CD4+ small/medium- T-cell LPD (SMPTCL) These lymphomas clinically present as a solitary plaque or tumour (Fig 9D) and are composed of dense, diffuse or nodular infiltrates of CD3+, CD4+, CD8 and CD30 small to medium-sized lymphocytes (Fig 9E) (Friedmann et al, 1995; von den Driesch & Coors, 2002). Recent studies have shown that SMPTCL may express follicular T-helper (FTH) cell markers, such as PD1, CXCL13,and BCL6, suggesting a role of the B-cell activation by FTH cells in some SMPTCL cases (Rodriguez Pinilla et al, 2009). Demonstration of an aberrant T-cell phenotype and clonality are useful criteria to differentiate SMPTCL from pseudo-t-cell lymphomas and benign infiltrates. The revised 2016 WHO classification acknowledges its indolent behaviour in changing the name of this entity to primary cutaneous CD4+ small/medium-sized pleomorphic T- cell lymphoproliferative disorder (Swerdlow et al, 2016). Surgical excision, low-dose radiotherapy and intralesional steroids are the preferred therapies (Table V) (Virmani et al, 2016). Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma This provisional entity presents with disseminated eruptive papules and/or tumours with central ulceration and overlying epidermal necrosis (Fig 8A), or with hyperkeratotic patches and plaques (Berti et al, 1999; Santucci et al, 2003). This is an aggressive lymphoma that may have visceral involvement, but lymph nodes are often spared. Histologically, it is characterized by an atypical lymphoid infiltrate with marked epidermotropism and expression of betaf1 and cytotoxic markers (granzyme B, perforin, TIA1). Invasion and destruction of adnexal structures is commonly seen and angiodestruction may also be present. The atypical lymphocytes are positive for CD3, CD8 and CD45RA, and negative for CD2, CD4, CD5 and CD45RO, with partial loss of CD7. Epstein Barr virus (EBV) is generally negative. Differentiation from other types of CTCL expressing a CD8+ cytotoxic T-cell phenotype (pagetoid reticulosis, rare cases of classic MF, LyP and PCALCL) is based on the pathology, clinical presentation and behaviour (Berti et al, 1999). The patients have a median survival of 32 months and are generally treated with doxorubicin-based multiagent chemotherapy, with consideration of consolidation by allogeneic stem cell transplantation (Table V) (Nofal et al, 2012). (A) (B) (c) Fig 8. Aggressive types of peripheral T-cell lymphoma (PTCL). (A) Patient with primary cutaneous CD8+ aggressive epidermotropic T-cell lymphoma presenting with disseminated ulcerated or erosive plaques on the back and extremities. (B) Patient with primary cutaneous gamma-delta T-cell lymphoma presenting with large ulceronecrotic plaques on the lower extremities. (C) Erythematous tumour on the left anterior wrist in a patient with PTCL-not otherwise specified. 26 ª 2016 John Wiley & Sons Ltd

12 (A) (D) (B) (E) Fig 9. Indolent types of peripheral T-cell lymphoma (PTCL). Patient with indolent CD8+ lymphoma of acral sites presenting with a single nodule on the right helix (A), that shows characteristically histological features of nonepidermotropic, monotonous, dermal infiltrate composed by small-sized T-cells [B (original magnification 94), C (original magnification 920)]. Clinical features of a CD4+ small medium-sized pleomorphic T-cell lymphoma presenting as a solitary and erythematous nodule on the left shoulder (D).Dense dermal infiltrate of small/medium lymphocytes admixed with numerous reactive cells (E, original magnification 940). (C) Cutaneous gamma/delta T-cell lymphoma (CGDTCL) Cutaneous gamma/delta T-cell lymphoma is a rare skin lymphoma composed of a clonal proliferation of gamma/ delta T-cells with a cytotoxic phenotype. Patients present with plaques and/or ulceronecrotic tumours on the trunk and extremities (Fig 8B), sometimes with mucosal involvement (Santucci et al, 2003). However, lymph nodes, spleen and bone marrow are usually spared. A subset of CGDTCL cases present with subcutaneous tumours showing a panniculitis-like pattern that may be complicated by a haemophagocytic syndrome (Gonzalez et al, 1991). Three major histological patterns are characteristic of CGDTCL: epidermotropic (mimicking MF), dermal and subcutaneous with rimming of fat cells. Frequently, more than one pattern is present in the same patient. The neoplastic T-cells are medium to large in size and positive for CD2, CD3 and CD56, and negative for CD4 and CD8. EBV expression can be seen in 25% of the cases and can lead to a misdiagnosis of extranodal NK/T-cell lymphoma (Yu et al, 2013). The differential diagnosis includes autoimmune disorders and psoriasiform dermatitis, but the atypical cells are positive for gamma/delta surface receptors and show clonal rearrangement of the T cell receptor gamma chain gene (TCR). Most patients have aggressive disease that is usually resistant to multiagent chemotherapy, with a median survival of only 15 months (Toro et al, 2003). The epidermotropic variant may present with a prolonged indolent behaviour. Allogeneic stem cell transplantation is a reasonable consideration at presentation (Table V) (Gibson et al, 2015). Good clinical responses to brentuximab vedotin have been recently reported in cases with relapsed/refractory disease (Talpur et al, 2016), and oral bexarotene is an option for patients with a more indolent/protracted course (Table V) (Hathaway et al, 2007). Activating STAT5B mutations occur in about a third of the cases which could represent a potential therapeutic target (Kucuk et al, 2015a). ª 2016 John Wiley & Sons Ltd 27

13 Indolent CD8+ lymphoid proliferation of acral sites This recently described entity presents with slow growth of solitary cutaneous papules and nodules, usually located on the ear (Fig 9A) but subsequent cases have been presented on the nose, hands and feet (Greenblatt et al, 2013; Li et al, 2014). Histologically, this condition is characterized by a non-epidermotropic, monotonous, dermal infiltrate composed by medium-sized T-cells with a Grenz zone (Fig 9B, C). The neoplastic cells are CD8+, TIA1+ and CD4, with a low proliferation index. T-cell receptor rearrangement studies show monoclonality in 50% of patients. After treatment with intralesional steroids, radiotherapy or surgery (Table V) (Virmani et al, 2016), local recurrences are seen but the prognosis remains excellent. Subcutaneous panniculitis-like T cell lymphoma (SPTCL) Subcutaneous panniculitis-like T cell lymphoma is a rare lymphoma that represents less than 1% of all CTCL. Clinically, it presents as solitary or multiple recurrent nodules, often located on the legs, with subcutaneous infiltrates of small to medium-sized atypical T-cells (Fig 10A, B). Systemic B-symptoms may be present and the disease may also be complicated by a haemophagocytic syndrome (Gonzalez et al, 1991). The neoplastic CD8+ T-cells are confined to the subcutaneous tissue producing panniculitis-like lesions, and characteristically express an a/b phenotype. Patients usually have a protracted clinical course with skin nodules that usually respond to systemic corticosteroids, methotrexate, spot radiation and oral bexarotene (Table V) (Willemze et al, 2008; Briki et al, 2010; Mehta et al, 2012). Nodal or systemic involvement is rare and the 5-year survival is greater than 80% (Massone et al, 2004). Cases that express a c/d phenotype are included in the category of cutaneous c/d T-cell lymphoma requiring systemic intervention. Extranodal NK/T-cell lymphoma, nasal type Extranodal NK/T-cell lymphoma is a rare type of CTCL that is more common in male patients from Asia, Central and South America. The skin is the second most common site of involvement after the nasal cavity/upper airway, but both presentations carry a poor prognosis with a median survival of less than 12 months. Patients present with multiple plaques and tumours on the trunk and extremities (Fig 11B) or with midfacial destructive nodules, known as lethal midline granuloma (Fig 11A). Histologically, this lymphoma shows dense dermal or subcutaneous infiltrates of small, medium-size or large lymphoid cells with an NK-cell phenotype (CD2+, CD56+) (Fig 11C, D) and expression of cytotoxic proteins (TIA-1, granzyme B, perforin). EBV is characteristically detected by EBV-encoded small RNAencoded small RNA (EBER) in situ hybridization in all cases (Fig 11E), indicating a pathogenic role for this infectious agent. Systemic chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) has not been effective, but the more recently developed SMILE regimen (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) or its modification has shown much better response and even long-term survival in systemic and relapsed disease (Table V) (Yang et al, 2013) and results improve following consolidation with autologous stem cell transplantation (Kim et al, 2015a). Molecular analyses have found frequent inactivation of tumour suppressor genes such as PRDM1, TP53, TP73, DDX3X and PTPN6 (SHP1). BCL2L11 (BIM) is quite often methylated and activating mutations of STAT3 and, less frequently, STAT5B have been described (Kucuk et al, 2015b). Primary cutaneous follicle centre lymphoma (PCFCL) Primary cutaneous follicle centre lymphoma is the most common B-cell lymphoma to occur as a primary tumour (A) (B) Fig 10. Patient with subcutaneous panniculitislike T-cell lymphoma presenting with dermal and subcutaneous nodules with overlying patches on the right leg (A). Subcutaneous infiltrate composed of small to medium-sized atypical T-cells with mild atypia and rimming of adipocytes is seen (B, original magnification 940). 28 ª 2016 John Wiley & Sons Ltd

14 in the skin and accounts for approximately 55% of all CBCL (Zinzani et al, 2006). It usually presents as solitary or grouped papules or nodules on head (Fig 12A), neck and trunk, sometimes with miliary papules and pustules. Skin lesions may be stable, enlarge slowly or regress in rare cases without treatment. Histologically, PCFCL shows a dermal and subcutaneous infiltrate of medium-sized to large centrocytes and centroblasts in a follicular and/or diffuse growth pattern (Fig 12B, C). The tumour cells express B-cell markers such as CD20 and CD79a, and are usually BCL6 positive and BCL2 negative (Suarez et al, 2013). Kappa or lambda light chain restriction is sometimes observed and molecular analysis reveals a monoclonal rearrangement of the IGH or IGK gene. The prognosis is excellent with a 5-year survival of 95%, but cutaneous relapses are observed in 30 45% of patients (Senff et al, 2007a). Treatment options include observation, intralesional steroids or rituximab injections, radiation or surgical excision. Rare cases with disseminated skin lesions should be treated with intravenous rituximab or chemoimmunotherapy (Table VI) (Rubegni et al, 1999; Senff et al, 2007b, 2008; Morales et al, 2008; Perry et al, 2010; Parbhakar & Cin, 2011; Penate et al, 2012). Primary cutaneous marginal zone lymphoma (PCMZL) Primary cutaneous marginal zone lymphoma is an extranodal marginal zone B-cell lymphoma that can develop from reactive infiltrates associated with chronic infections or autoimmune processes. The skin is the second most common site of involvement by these lymphomas after the gastric mucosa. PCMZL presents as solitary red or violaceous papule, plaque or nodule most commonly on the extremities (Fig 13A), usually in young adults but also in children. The differential diagnosis includes arthropod bites or hives, medicationinduced pseudolymphoma and basal cell carcinoma if the lesions are located on the face (Suarez et al, 2013). The association with Borrelia burgdorferi infection has been reported in Europe but not in Asia or the United States (Cerroni et al, 1997; Wood et al, 2001). This is an indolent lymphoma with a 5-year survival of up to 99%, but cutaneous relapses are noted in 40% of patients. Histologically, PCMZL consists of a nodular or diffuse infiltrate of small B-cells with clear cytoplasm, sometimes with abundant plasma cells, along with admixed reactive T-cells and scattered large cells (Fig 13B, C). The neoplastic cells are CD20, CD79a and BCL2 positive, and are negative for CD10 and BCL6. Plasma cells are often (A) (C) (B) (D) Fig 11. Natural Killer-T-cell lymphoma,also known as lethal midline granuloma, presenting as ulceration of palate (A). Erythematous and violaceous tumours on the anterior chest and abdomen (B). A dense subcutaneous infiltrate of large lymphoid cells expressing CD56 (C, D). Epstein Barr virus (EBV) is characteristically positive by EBV-encoded small RNAencoded small RNA (EBER) in situ hybridization (E). Panels C, D, E: original magnification 940. (E) ª 2016 John Wiley & Sons Ltd 29

15 (A) (B) (C) Fig 12. Patient with primary cutaneous follicle-centre lymphoma presenting with an erythematous and infiltrated plaque on the right cheek and inner canthus (A). Dermal and subcutaneous infiltrate of medium-sized to large centrocytes and centroblasts in a follicular and diffuse growth pattern [B (original magnification 910), C (original magnification 940)]. Table VI. Summary of treatments and response for patients with primary cutaneous B-cell lymphomas (PCBCL). PCBCL subtype Treatment Response Indolent entities PCFCL and PCMZL Solitary and/or localized skin lesions Observation Intralesional steroids Local radiation Surgical excision Intralesional interferon-a Intralesional rituximab ORR 100%, CRR 44% CRR100% CRR 71%, PRR 23% Disseminated skin lesions Observation IV rituximab Chemoimmunotherapy (R-Bendamustine) ORR 87%, CRR 60% CRR 85% Cases associated with Lyme disease Aggressive entities PCDLBCL-LT Systemic antibiotics (doxycycline, cefotaxime) Chemoimmunotherapy (R-CHOP) Chemoimmunotherapy + RT (localized disease) Palliative RT (localized disease) Autologous stem cell transplant (relapse/ refractory cases) Lenalidomide Clinical trials: Aurora kinase inhibitors, ofatumumab, lumiliximab, dacetuzumab, Ibrutinib, pembrolizumab. Based on EORTC guidelines, isolated cases with CR CRR 92% Isolated cases with CR ORR 20% PCFCL, primary cutaneous follicular lymphoma; PCMZL, primary cutaneous marginal zone lymphoma; PCDLBCL-LT, primary cutaneous diffuse large B-cell lymphoma, leg type; ORR, overall response rate; CRR, complete response rate; PRR, partial response rate; CR, complete response; EORTC, European Organization for Research and Treatment of Cancer; CR, complete response; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; R, Rituximab; RT, radiation therapy. clonal and the IGH/ MALT1 translocation is observed in 33% of the cases (Palmedo et al, 2007). Treatment approach is the same as for patients with PCFCL, except that cases associated with Lyme disease require systemic antibiotics (Table VI) (Kutting et al, 1997). Primary cutaneous diffuse large B-cell lymphoma, leg type (PDLBCL- LT) Primary cutaneous diffuse large B-cell lymphoma, leg type, is the only subtype of CBCL that carries a poor prognosis, with 30 ª 2016 John Wiley & Sons Ltd

16 a 5-year survival of only 50%. Patients usually present with red to violaceous, rapidly growing tumours on one (Fig 14A) or both legs. However, 10 15% of the cases present with skin lesions in locations other than the lower extremities, which carries a better prognosis (Grange et al, 2007). On histology, PDLBCL-LT shows a diffuse dermal proliferation of centroblasts and/or immunoblasts (Fig 14B) that are CD20+ and CD79+ and sometimes express cytoplasmic immunoglobulins. This is a skin lymphoma with a non-gcb phenotype but rare development from PCFCL is reported (Dias Coelho et al, 2010). Essential components of the work-up for CBCL are summarized in Table II. Bone marrow biopsy is indicated in PDLBCL-LT and PCFCL, but is optional in PCMZL. PCDLBCL-LT patients should be treated with anthracycline-based chemotherapy plus the anti-cd20 monoclonal antibody rituximab (Willemze et al, 2005), but relapses are commonly seen after chemoimmunotherapy induction. Consolidation with autologous stem cell transplant has achieved complete remission in selected cases, but further studies are needed before definitive recommendations can be made (Table VI) (Goto et al, 2005; Grange et al, 2007; Fenot et al, 2010; Roschewski et al, 2012). PCDLBCL-LT strongly expresses BCL2, MUM1 (Fig 14C) and FOXP1, similar to the expression profile of other postgerminal centre (post-gc) or activated B-cell type of DLBCL, whereas PCFCL does not show this profile and belongs to (A) (B) (C) Fig 13. Patient with primary cutaneous marginal zone lymphoma showing a solitary erythematous nodule involving the right anterior forearm (A). Diffuse infiltrate of small B-cells with clear cytoplasm, along with admixed reactive T-cells and scattered large cells [B (original magnification 910), C (original magnification 960)]. (A) (B) (C) Fig 14. Patient with primary cutaneous diffuse large B-cell lymphoma, leg-type presenting with a red to violaceous, rapidly growing ulcerated tumour on the right anterior leg (A). Diffuse dermal and subcutaneous proliferation of centroblasts and immunoblasts (B, original magnification 940). The neoplastic cells strongly express MUM1 (C). ª 2016 John Wiley & Sons Ltd 31