Lymphoma: Review Article

Cutaneous T‑cell lymphomas and their management strategies Pandey SS, Garg S1, Dwivedi AND2, Tripathi R3, Tripathi K1, Bansal M Departments of Dermatology and Venereology, 1General Medicine, 2Radiodiagnosis and Imaging, and 3Oral and Maxillofacial Surgery, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India Correspondence to: Dr. Manish Bansal, E‑mail: [email protected]

Abstract Cutaneous T‑cell lymphomas (CTCLs) comprise a heterogeneous group of lymphoproliferative disorders characterized by the proliferation of skin‑homing post‑thymic T‑cells. It is the second most common extranodal non‑Hodgekin’s lymphoma. Many variants of mycosis fungoides and CTCLs are known to date, differing in clinical, histological, and immunophenotypic characteristics. Oral involvement has also been reported rarely in CTCLs. Treatment depends on the disease stage or the type of variant. New insights into the disease and the number of emerging novel therapeutic options have made it an interesting area for dermatologists and medical oncologists. Key Words: Cutaneous T‑cell lymphomas, management, mycosis fungoides, review, systemic retinoids

Introduction Cutaneous T‑cell lymphomas (CTCLs) are a heterogeneous group of lymphoproliferative disorders characterized by clonal proliferation of malignant, mature, skin‑infiltrating T lymphocytes.[1] CTCLs represent 65% of primary cutaneous lymphomas, with mycosis fungoides (MF) being the most common form, representing two‑third of all CTCLs and almost 50% of all primary cutaneous lymphomas. In the United States, the incidence rate is increasing very rapidly and it is the second most common group of extranodal non‑Hodgkin lymphomas, after the primary gastrointestinal lymphomas. Latest classification of lymphomas as proposed in 2008 is described in Table 1.[2] In CTCLs, there is a clonal proliferation of skin‑homing lymphocytes, further characterized by skin localization, avoidance of bone marrow even during high leukemic counts, and infiltration of perifollicular T‑cell zones of lymph nodes and spleen. The regulating receptors include cutaneous lymphocyte antigen acting as a ligand for E‑selectin, intracellular adhesion molecule 1 with its ligand leukocyte function antigen, and chemokine receptor CCR4 with its ligand thymus and activation‑regulated chemokine.[3,4] The role of oncogenes has also been studied in the pathogenesis of CTCLs. Transcription factors of the nuclear factor κβ, signal transducer and activator of transcription (STAT) gene families, oncogenes such as c‑myb, c‑myc/max, and junD are constitutively active.[5‑8] These are involved in the regulation of cell survival genes, potential targets being bcl‑2, bcl‑xL, mcl‑1, and CD25. Cell death promoting Bad and Bax proteins are inactivated in CTCLs.[9] Increased proliferation rate can be attributed to high levels of c‑myc and junD molecules (stimulate the transition from the G0 to G1 stage), expression of bmi‑1 and Ki‑ras oncogenes (repressor of p16), and phosphorylation at CDK4 and 6 specific sites (inactivation of Rb). [8] Recent studies have shown NAV3 gene mutations at 12q2, which has helicase‑like activity and may contribute to genomic instability.[10] Studies on the role of environmental factors and chemical Access this article online Quick Response Code:

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agents on CTCL have yielded mixed results. Early epidemiologic studies and a multicenter European study showed an association, but some studies have failed to provide an evidence for the same.[11‑13] The disease occurs more commonly in the elderly and immunosuppressed individuals, such as after organ transplantation.[14,15] The role of staphylococcal infection in triggering CTCL carcinogenesis and promoting disease progression has been studied. [16,17] The role of human T‑lymphotropic virus (HTLV) as a cause of adult T‑cell leukemia and lymphoma was discovered; however, large subsequent studies almost ruled out HTLV as a cause of CTCL.[18] Repeated detection of retrovirus‑like particles and reverse transcriptase activity in patients with CTCL suggest a possible involvement of an alternate retrovirus.[19,20] Among herpesviruses, studies support a role of Epstein‑Barr virus (EBV), Kaposi sarcoma‑associated herpesvirus (human herpesvirus [HHV] 8) and cytomegalovirus in disease pathogenesis, but current data fail to support a role for HHV‑6 and HHV‑7.[21‑24] Mycosis Fungoides MF shows a male preponderance (male:Female ratio 2:1) and mostly develops after the fourth decade in life, except in 1.8‑7% of the cases that develop at an early age and show a characteristic female preponderance.[25‑28] It was first described by Alibert in the 19 th century due to its mushroom‑like appearance. Initial lesions are nonspecific eczematous patches followed by the more specific plaque and tumor stage, except for 10% of patients that directly manifest with tumor (d’emblee form). A papillary dermal infiltrate with small‑to medium‑sized lymphocytes with hyperchromatic and hyperconvoluted nuclei is the characteristic histological feature. [29] Epidermotropism seen in the plaque stage is usually lost in the tumor stage. Phenotype of neoplastic cells is typically CD2+, CD3+, CD4+, CD5+, TCRβ+, CD45RO+, CD8−, and CD 30−. Most cases are of the helper/inducer T‑cell subset expressing the CD4−/CD8+  phenotype, but there is a loss of T‑cell receptors with disease progression or transformation. Poor prognostic factors are advanced stage and old age. Less than 1‑year survival is observed in extracutaneous involvement or transformation of CTCLs (8‑55% of patients) to high‑grade lymphomas.[30,31] Sézary Syndrome The term was proposed by Taswell and Winkelmann in 1961. [32] In 1938, Sézary and Bouvrain described the 293

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Table 1: Contd...

Table 1: World Health Organization (WHO) 2008 classification of lymphomas Mature B‑Cell Neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma B‑cell prolymphocytic leukemia Splenic marginal zone lymphoma Hairy cell leukemia Splenic lymphoma/leukemia, unclassifiable Splenic diffuse red pulp small B‑cell lymphoma* Hairy cell leukemia‑variant* Lymphoplasmacytic lymphoma Waldenström macroglobulinemia Heavy chain diseases Alpha heavy chain disease Gamma heavy chain disease Mu heavy chain disease Plasma cell myeloma Solitary plasmacytoma of bone Extraosseous plasmacytoma Extranodal marginal zone B‑cell lymphoma of mucosa‑associated lymphoid tissue (MALT lymphoma) Nodal marginal zone B‑cell lymphoma (MZL) Pediatric type nodal MZL Follicular lymphoma Pediatric type follicular lymphoma Primary cutaneous follicle center lymphoma Mantle cell lymphoma Diffuse large B‑cell lymphoma (DLBCL), not otherwise specified T cell/histiocyte rich large B‑cell lymphoma DLBCL associated with chronic inflammation EBV+DLBCL of the elderly Lymphomatoid granulomatosis Primary mediastinal (thymic) large B‑cell lymphoma Intravascular large B‑cell lymphoma Primary cutaneous DLBCL, leg type ALK+large B‑cell lymphoma Plasmablastic lymphoma Primary effusion lymphoma Large B‑cell lymphoma arising in HHV8‑associated multicentric Castleman disease Burkitt lymphoma B‑cell lymphoma, unclassifiable, with features intermediate between diffuse large B‑cell lymphoma and Burkitt lymphoma B‑cell lymphoma, unclassifiable, with features intermediate between diffuse large B‑cell lymphoma and classical Hodgkin lymphoma Hodgkin Lymphoma Nodular lymphocyte‑predominant Hodgkin lymphoma Classical Hodgkin lymphoma Nodular sclerosis classical Hodgkin lymphoma Lymphocyte‑rich classical Hodgkin lymphoma Mixed cellularity classical Hodgkin lymphoma Lymphocyte‑depleted classical Hodgkin lymphoma Mature T‑Cell Neoplasms T‑cell prolymphocytic leukemia T‑cell large granular lymphocytic leukemia Chronic lymphoproliferative disorder of NK‑cells* Aggressive NK cell leukemia Systemic EBV+T‑cell lymphoproliferative disease of childhood (associated with chronic active EBV infection) Hydroa vacciniforme‑like lymphoma Contd...

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Adult T‑cell leukemia/lymphoma Extranodal NK/T cell lymphoma, nasal type Enteropathy‑associated T‑cell lymphoma Hepatosplenic T‑cell lymphoma Subcutaneous panniculitis‑like T‑cell lymphoma Mycosis fungoides/Sézary syndrome Primary cutaneous CD30+T‑cell lymphoproliferative disorder Lymphomatoid papulosis Primary cutaneous anaplastic large‑cell lymphoma Primary cutaneous aggressive epidermotropic CD8+cytotoxic T‑cell lymphoma* Primary cutaneous gamma‑delta T-cell lymphoma Primary cutaneous small/medium CD4+T-cell lymphoma* Peripheral T‑cell lymphoma, not otherwise specified Angioimmunoblastic T‑cell lymphoma ALCL, ALK+ ALCL, ALK−* *Provisional entities for which the WHO working group felt there was insufficient evidence to recognize as distinct diseases at this time. MALT=Mucosa associated lymphoid tissue; MZL=Marginal zone lymphoma; DLBCL=Diffuse large B‑cell lymphoma; EBV=Epstein‑barr virus; ALK=Anaplastic lymphoma kinase; HHV=Human herpesvirus; NK=Natural killer cells; CD=Cluster of differentiation; ALCL=Anaplastic large cell lymphoma

mononuclear cells with hyperconvoluted atypical nuclei, for which they used the term “cellules monstreuses” or “monster cells” (now called as Sézary or Lutzner cells).[33] Distinct clinical features are erythroderma, palmoplantar hyperkeratosis, onychodystrophy, and lymphadenopathy. The most prevalent histologic finding is superficial perivascular infiltrate of small lymphoid cells. The rest of the features are similar to those of MF, although Pautrier’s collections and acanthosis are more common in SS.[34,35] There is a Th1/Th2 imbalance with type 2 response predominating, followed by impaired cell mediated cell‑mediated immunity.[36] There is loss of T‑cell antigens in 66% of cases, CD2 being the most common.[37] The percentage of CD4+  CD7−  cells correlates with Sézary cell count. [38] According to the diagnostic criterion proposed by International Society for Cutaneous Lymphoma, one or more of the following should be present:[1] An absolute Sézary cell count of at least 1000 cells/mm3 in the peripheral blood;[2] CD4/CD8 ratio greater than 10:1; [3] an aberrant loss/expression of pan – T‑cell markers (CD2, CD3, CD4, CD5, CD7) by flow cytometry;[4] evidence of a T‑cell clone in blood with increased leukocyte count; and[5] chromosomal abnormality in the T‑cell clone.[39] Extracorporeal photopheresis is the first‑line therapy with response rates of up to 87%. [40] Chemotherapy with methotrexate alone or combination regimens including chlorambucil and prednisolone are also effective.[41,42] Prognosis is poor in most cases, with 5‑year survival rates of 33%.[43] Poor prognostic factors include presence of very large Sezary cells (>14 micrometer in diameter) and lack of expression of CD7.[44,45] The recommended staging system for MF/SS is according to the tumor, node, metastasis, blood (TNMB) classification [Table 2]. Variants of MF are: • Pagetoid Reticulosis: Two forms are mainly described, unilesional (superficial spreading or Woringer–Kolopp Indian Journal of Cancer | July–September 2014 | Volume 51 | Issue 3

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Table 2: Tumor, node, metastasis, blood classification for mycosis fungoides/sézary syndrome T (skin) T1 T2 T3 T4 N (nodes) N0 N1 NP0 NP1 LN0 LN1 LN2 LN3 LN4 M (viscera) M0 M1 B (blood) B0 B1

Limited patch/plaque (10% of BSA) Tumors Generalized erythroderma No clinically abnormal peripheral lymphnodes Clinically abnormal peripheral lymphnodes Biopsy performed, not CTCL Biopsy performed, CTCL Uninvolved Reactive lymph node Dermatopathic node, small clusters of convoluted cells (6 cells per cluster) Lymph node effacement No visceral metastasis Visceral metastasis Atypical circulating cells not present Atypical circulating cells present

*Pathologically involved lymph nodes; BSA=Body surface area; CTCL=Cutaneous T‑cell lymphomas

disease) or disseminated. Clinically, it appears as psoriasiform plaque on acral body areas. Mucosal involvement is rare. [46] Disease dissemination to other organs, lymph nodes, peripheral blood, and bone marrow is not seen. Appearance of medium to large atypical lymphoid cells with vacuolated, abundant cytoplasm disaggregating into epidermis is the histologic hallmark. [47] Rapidly proliferating neoplastic cells (proliferation rate > 30% as compared to 50%) of CD30+ cells differentiate it from typical MF[46] • Syringotropic cutaneous T‑cell lymphoma: It is characterized by anhidrosis and hair loss in affected areas due to neoplastic cells infiltrating the eccrine glands and destroying the hair follicles (syringolymphoid hyperplasia with alopecia).[48,49] Other atypical variants of MF include follicular, bullous, granulomatous, hypopigmented, poikilodermic, hyperpigmented, hyperkeratosis, and vegetating. Variants of Cutaneous T‑cell Lymphomas • Granulomatous cutaneous T‑cell lymphomas: These include the granulomatous variants of MF and SS and granulomatous slack skin. Although they run a slow progressive course, 50% may have a fatal outcome due to nodal lymphomas. The latter was first described in 1968 by Bazex et  al. as “chalazodermie granulomateuse” and the term was introduced by Ackerman in 1978. [50,51] There is destruction of elastic fibers in Indian Journal of Cancer | July–September 2014 | Volume 51 | Issue 3

intertriginous and flexural areas, resulting in bulky and pendulous axillay and inguinal folds (cutis laxa‑like appearance). On histology, there is less‑pronounced nuclear atypia with the presence of multinucleated, giant syncytial cells (containing up to 40 nuclei) causing elastophagolysis and emperipolesis (phagocytosis of lymphoid cells with giant cells). Histiocytic markers such as CD68 and Mac387 are positive. Therapeutic options are psoralen with ultraviolet A (PUVA) therapy, surgical excision or interferon alfa in combination with retinoids. Although the course is indolent, 30% of patients develop other lymphomatoid malignancies • CD30+  T‑cell lymphoproliferative disorders: The hallmark of this category is the expression of CD30, a cytokine receptor belonging to the tumor necrosis factor receptor superfamily. It includes lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T‑cell lymphoma. • Lymphomatoid Papulosis: Described in 1968 by Macaulay, it is a chronic, recurrent, self‑healing papulo‑nodular skin eruption of unknown etiology, often leaving behind hyper‑or hypopigmented scars on regression.[52] Lesions most often arise on the trunk, buttocks, and extremities. Three histologic variants have been described: Type A (extensive inflammatory infiltrate comprising scattered CD30+  blast cells), Type  B  (atypical CD30−  T‑cells with cerebriform nuclei simulating classical MF), and Type C (few inflammatory cells with numerous CD30+ cells). Proliferation of T‑helper cells is represented by the expression of HLA‑DR and CD25 (interleukin 2 receptor).[53,54] Clonal TCR gene rearrangement has been variably detected. Although it cannot be cured, methotrexate can clear the skin lesions in 90% of the patients.[55] They usually run a benign course with 5‑year survival rates of 100% but may lead to second lymphoid neoplasm in 5‑15% of cases.[56] • Primary cutaneous anaplastic large cell lymphoma (ALCL) : According to European Organisation for Research and Treatment of Cancer (EORTC) classification, these are defined by CD30 expression of at least 75% of large pleomorphic or anaplastic lymphoid cells.[57] With a prevalence of 1‑2 per million, it is the second most common form of cutaneous lymphoma. The most common presentation is rapidly growing tumors on the extremities and the head, with spontaneous regression noticed in 10‑42% of lesions. [58] Histological features are the presence of large cells with an abundant clear cytoplasm containing irregular nuclei with one or more nucleoli. Neutrophil‑rich ALCL (N‑ALCL) is an ulcerative variety of lesion characterized by purulent secretions from small abscesses. [59,60] Most nodal and only a few primary cutaneous ALCLs have a t(2;5) (p23;q35), causing the expression of nucleoplasmin‑anaplastic lymphoma 295

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kinase (NPM‑ALK) protein, thereby resulting in a better prognosis.[61] Relationship with Hodgkin’s disease has been detected, as both have JunB overexpression. Prognosis is good, with a 5‑year survival rate of 90%.[56] Better prognosis is observed with spontaneous regression (seen in 40% of the cases) and age less than 60 years. Poor prognosis is observed with the coexpression of CD56 and CD30, point mutations and deletions on TGF‑β receptor genes I and II, and increased levels of fascin. [62‑64] The preferred mode of therapy is with spot radiation or surgical excision, with chemotherapy reserved for refractory cases. • Subcutaneous panniculitis‑like T‑cell lymphoma: There are multiple indurated lesions in the subcutaneous fat tissue, located on the lower legs resembling panniculitis. [65‑67] Cytokines such as tumour necrosis factor (TNF) alpha and interferon gamma are released, leading to a hemophagocytic syndrome with resulting cytopenia. [68] Large and in‑depth biopsy subjected to histopathological examination reveals subcutaneous, nonepidermotropic, focal infiltrates simulating panniculitis with the presence of karyorrhexis and fat necrosis.[66,67] Most cases in Asians are associated with EBV, which also plays a role in the development of hemophagocytosis.[69] T cell receptor (TCR) α/β cases exhibit an indolent, slowly progressive course compared with γ/δ cases, which have a rapid and aggressive course. [70,71] The prognosis is generally poor, with an overall survival (OS) rate of less than 3 years on aggressive chemotherapy. • Primary cutaneous peripheral T‑cell lymphoma, unspecified: This entity includes two subtypes: • Cytotoxic Lymphomas: This is a heterogeneous class including CD8+ T‑cell, T/NK‑cell, and NK‑cell lymphomas and myelomonocytic leukemia. Tumor cells display cytotoxic proteins such as perforin (cytolysin), serine esterases (granzymes), and granule‑membrane‑associated cytotoxic protein TIA‑1, leading to primary or secondary cutaneous involvement. TIA‑1 is expressed in activated and non‑activated NK cells and cytotoxic T‑cells and serves as a useful marker to identify cytotoxic lymphocytes.[72,73] • Noncytotoxic Lymphomas: It includes primary cutaneous CD4+ small to medium‑sized pleomorphic T‑cell lymphoma. It is a provisional entity in EORTC classification and only a few cases have been reported. • Extranodal NK/T‑cell Lymphoma, Nasal Type: There is a considerable heterogeneity in clinical, histological, and immunophenotypic features among extranodal NK/T‑cell lymphomas; however, the common feature is CD56 expression by the tumor cell.[74] Classic nasal type is more frequent in Asia and Latin America and is associated with EBV. Large nasal ulcerations in this disease led to the old term “lethal midline granuloma”.[75] Angiocentric and angiodestructive growth patterns and azurophilic granules containing cytotoxic molecules are 296

characteristic findings.[75] Polychemotherapy followed by bone marrow transplantation is the treatment. • Adult T‑cell Leukemia/Lymphoma  (ATLL): It is a peripheral T‑cell lymphoma associated with human T‑cell leukemia virus 1 (HTLV‑1) that is endemic in southwestern Japan and Caribbean. [76‑78] Skin involvement is seen in 50% of patients. Associated features are hypoalbuminemia, hypergammaglobulinemia, and hypercalcemia. Bone marrow involvement, lymphadenopathy, hepatospleenomegaly, and pulmonary infiltrates are also observed. Atypical lymphoid cells with convoluted nuclei (thus called flower cells) are detected on peripheral blood smears. The p40 tax protein of HTLV‑1 that causes transcriptional activation is one of the main pathogenetic factors in ATLL. [79] Most patients are treated with multiagent chemotherapy, with a high tumoricidal activity seen with the combination of zidovudine and interferon alfa.[80] • Angioimmunoblastic T‑cell Lymphoma: Frizzera et al. identified this entity in the early 1970s and used the term angioimmunoblastic lymphadenopathy with dysproteinemia or immunoblastic lymphadenopathy.[81] It is a systemic disease, with skin involvement occurring in 50% of cases, in the form of maculopapular rash resembling viral exanthem. Atypical lymphoid cells are present, with the proliferation of high endothelial venules and follicular dendritic cells, leading to non‑specific superficial perivascular dermatitis and vasculitis. Staining for factor XIIIa reveals increased dendritic cells. Course is aggressive with mortality ranging from 50% to 70%. EBV has been identified in skin lesions. and patients often succumb to EBV‑positive B‑cell nodal lymphomas.[82] Oral Manifestations of Cutaneous T‑cell Lymphomas Lymphomas represent the third most common group of malignant lesion of the oral region following squamous cell carcinoma and salivary gland neoplasm. Their incidence is only 3‑5% in the oral cavity.[83] Two independent studies performed on CTCL patients at autopsy revealed oral MF lesions in 7% and 22% of the patients, respectively.[84,85] A trial carried out from 1968 to 1993 showed only 8 out of 824 patients to have the disease (an incidence of less than 1%). [86] This disparity between the autopsy and clinical cases reflects the high frequency of subclinical or missed cases of the disease. Clinical Features Waldeyer’s ring, which consists of the nasopharynx, tonsils, and the base of the tongue, is the most common location for malignant lymphoma in the head and neck region. Lymphomas occurring in the head and neck generally present intranodally. The most common reported sites of MF oral involvement are the tongue and palate.[87] Clinical presentation is varied, and includes ulcerated tumors, indurated plaques, papules, leukoplakia‑like lesions, nodules, and multiple erosions. [85‑89] The surfaces of CTCL are characterized by an absence of epithelial hyperplasia and may become plaque‑like and indurated; central necrosis marks Indian Journal of Cancer | July–September 2014 | Volume 51 | Issue 3

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the later stages of the disease process. [90] Patients often report with localized facial swelling or painful non‑healing ulcer in the facial region. Dysphagia and odynophagia arise commonly, on average, 8 years after the onset of cutaneous symptoms.[87,91] Management Differential diagnosis include geographic tongue, trauma, benign eosinophilic ulcers of the oral mucosa, lymphomatoid papulosis,[92] malignancies, and infection. Since the systemic signs may not be evident, the diagnosis of facial cutaneous lymphoma is difficult by clinical examination alone. A biopsy and culture is necessary for a definitive diagnosis. Histologically, oral lesions resemble the cutaneous lesions, with the typical findings being features of band‑like infiltrates of atypical lymphocytes, Pautrier’s microabscesses, and exocytosis.[89,91] Oral involvement in CTCLs is an indicator of poor prognosis, with a mean survival time of 9.6 months from oral lesions presentation. [85] Almost 50% of the patients expire within 1 year, and 100% within 3 years.[86] Historically, potassium iodide and excision have been used for the treatment of oral lesions. [91] Presently, systemic chemotherapy and brachitherapy are the preferred modes of treatment, although lesions may recur.[91,93] Surgical therapy is reserved for cases of gross facial disfigurement. Treatment of Cutaneous T‑cell Lymphomas CTCL usually has an indolent course but can become symptomatic and cosmetically disfiguring, which has a profound effect on the patient’s quality of life. Disease stage determines the prognosis and duration of survival and the treatment modality. In early disease stages, skin‑directed therapies are generally first‑line treatment, whereas systemic therapies are used for advanced disease stages or as a second‑line therapy to topical agents. Appropriate treatment choices according to disease stage have been provided by recommendations from EORTC, German Cancer Society, and the joint British Association

of Dermatologists and UK Cutaneous Lymphoma Group [Table 3]. Skin‑directed Therapy In patients with stage IA and IB disease, 60% respond effectively in the long term with skin‑directed therapy. Topical corticosteroids can induce clinical remission in 25‑63% of patients, mainly by inhibiting lymphocytic bonding to the endothelium and inducing cell death by upregulating the proapoptotic genes. [94] Topical mechlorethamine has been shown to produce complete response (CR) rates of 26% to 76% in patch/plaque stage and 22‑49% in stage III disease. [95‑97] Contact hypersensitivity and secondary cutaneous malignancies are common side effects. [98] Topical carmustine is used less frequently owing to its side effects of myelosuppression (30%) and telengiectasia. Topical retinoids have shown efficacy in stage IA and IB disease resistant to other topical therapies. Bexarotene (Targretin) was introduced in both topical and oral formulation. It is a highly selective retinoid X receptor (RXR) that binds to RXR‑γ and RXR‑α receptors and alters gene transcription. [99] Almost 12% patients had contact dermatitis on application. Phototherapy with PUVA (oral methoxypsoralen with ultraviolet A light) is most commonly used. It induces apoptosis of the infiltrating tumor cells and mononuclear cells, including Langerhans cells. [100,101] Of the 63% of patients who responded, 50% showed sustained remissions. [101] UVB, which penetrates only the dermis, has been used widely in CTCL, with narrowband UVB (311‑313 nm) being more effective than broadband UVB (290‑320 nm). [102‑104] Combination regimens with PUVA and interferon alpha are more effective than a combination of interferon alfa and acitretin in stage I or II disease. Electron beam radiotherapy is an effective therapy for patients with all stages of MF. It uses electrons

Table 3: Treatment algorithms according to disease stage Stage

Initial therapy

IA

Skin‑directed therapy

IB/2A

Skin‑directed therapy±biologic therapyb Skin‑directed therapy PUVA, electron beam radiation therapy+biologic or single‑agent therapyc

IIB

Relapsed/refractory disease a

Additional skin‑directed therapy or skin‑directed therapy with biologic or single‑agent therapy Skin‑directed therapy+biologic or single‑agent therapy

IIIA/B

ECP±or skin‑directed therapy Multimodality combinations with systemic or biologic therapies

Multimodality combinations: Skin‑directed therapy+single‑agent chemotherapy or biologic therapy Multiagent therapy Allogeneic stem cell transplantation Multimodality combinations with single‑agent or multiagent therapy Allogeneic stem cell transplantation

IVA/B

Single‑agent chemotherapy, combination biologic therapy Multiagent therapyd

Salvage chemotherapy Allogeneic stem cell transplantation

Skin‑directed therapy: Topical steroids (intermediate and high potency), topical nitrogen mustard or bischloroethylnitrosourea ointment or aqueous solution, topical retinoids (bexarotene gel, tazarotene gel), phototherapy (UVB for patch or thin plaque, PUVA for thick plaque), electron beam irradiation (localized for limited disease, total skin for extensive skin involvement); bBiologic therapies: Interferon‑α, retinoids (bexarotene, 13‑cis retinoic acid, all‑trans‑retinoic acid), ECP, alemtuzumab; c Single‑agent therapy: Methotrexate (low‑dose oral or intravenous), denileukin diftitox, HDAC inhibitor (vorinostat), liposomal doxorubicin, gemcitabine, pentostatin, etoposide, cyclophosphamide, bortezomib, temozolomide; dMultiagent combination therapies: Biologic combinations (PUVA, UVB, or ECP+retinoids or interferon; PUVA UVB, ECP+retinoids+interferon; denileukin diftitox+bexarotene; retinoids+interferon; PUVA, UVB, or ECP with HDAC inhibitor [under investigation]); cytotoxic multiagent regimens (gemcitabine, venorelbine; liposomal doxorubicin; etoposide, vincristine, doxorubicin, cyclophosphamide, and oral prednisone; hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone, alternating with methotrexate and cytarabine; etoposide, methylprednisolone, cytarabine, cisplatin; ifosfamide, carboplatin, etoposide). ECP=Extracorporeal photopheresis; PUVA=Psoralens with ultraviolet A therapy; UVB=Ultraviolet B; HDAC=Histone deacetylases a

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ranging in energy between 4‑7 MeV with limited skin penetration (80% of dose administered within the first 10 mm of depth). Total skin electron beam therapy (TSEB) is used in patients with extensive patches or thin plaques refractory to other skin‑directed therapies. CR for patients with patch or plaque stage ranges from 71% to 98%. Side effects reported are secondary cutaneous malignancies, pruritus, alopecia, xerosis, and telengiectasias. Systemic Therapy Immunomodulator therapy

Extracorporeal photopheresis (ECP) is effective in both SS and in tumor and plaque stage of CTCL. This process involves the exposure of approximately 10 10 peripheral blood mononuclear cells to photoactivated 8‑methoxypsoralen leading to cross‑links of the sister strands of deoxyribonucleic acid (DNA) by binding to thymidine, leading to apoptosis of lymphocytes. Monocytoid cells, which are spared during the process, differentiate into immature dendritic cells that uptake and process the tumor antigens. [105] Frequency of administration may be either for two consecutive days per month or for every 2 weeks, continued until maximal clearing. In 1973, a study achieved a response rate of 73% in patients who had refractory MF/SS. [106] Administration of granulocyte‑macrophage colony‑stimulating factor following each ECP treatment to enhance antigen‑presenting cell function can be practiced. Transimmunisation is a modification of ECP in which the malignant T‑cells and newly formed dendritic cells are co‑incubated to stimulate a more efficient tumor‑targeted therapy.[107‑110] Cytokine‑based therapies have been explored in CTCLs based on the dysregulated Th1/Th2 response seen in the disease. Early MF lesions carry a Th1 profile, whereas SS lesions exhibit a Th2 profile.[111] As a result of Th2 response, IL‑4, IL‑6, and IL‑10 are produced, which inhibit cytotoxic T‑cell responses by inhibiting interferon‑γ production. Interferon‑γ showed an Overall Response Rate (ORR) of 30% and a Duration of Response (DOR) of 10 months when used as a monotherapy in 16 patients with refractory disease.[112] Interferon‑α (IFNα) increases MHC‑I expression on lymphocytes, suppresses Th2 cytokine production, and induces IL‑15 to cause activation of CD8 + T‑cells and natural killer cells.[113,114] Doses range from 1 to 18 mU, which are administered subcutaneously, usually 3 times a week. Studies with the drug showed 73% response in stage IA‑IIA and 60% response in stage IIB‑IVA.[115] Combination regimens with IFNα and PUVA showed superiority over other regimens and resulted in high response rates. [115] Cytosine phosphodiester guanine (CpG) oligonucleotides have emerged as a novel immunomodulatory therapy that targets multiple immune effector cells. Toll‑like receptor 9 agonist CPG7909 is an example, phase I study of which showed an ORR of 25%.[116] Retinoids

Systemic retinoids are the first systemic agents for advanced or refractory MF/SS. Oral bexarotene is a highly selective RXR‑binding retinoid having proapoptotic 298

and immunomodulatory effects. In doses of 300 mg/m2 administered daily, it had a response in 54% of patients with refractory early disease and 45% of patients with refractory advanced disease, with a median duration of response of 299 days. [117] Side effects include elevation in serum lipids and hypothyroidism. Hyperlipidemia occurs rapidly within 2‑4 weeks and hypothyroidism is central and dose‑dependent. Supplementation with hypolipidemic drugs and levothyroxine may be considered; however, the condition usually reverts within 1‑2 weeks after discontinuation. Denileukin diftitox

Denileukin diftitox (Ontak) combines Interleukin 2 (IL 2) with a cytocidal moiety, such as truncated diphtheria toxin (DAB389) as the toxophore. IL 2R is overexpressed in most patients of adult T‑cell leukemia and in 50% of the patients with CTCL. This molecule undergoes receptor‑mediated endocytosis into tumor cells and inhibits protein synthesis via ADP‑ribosylation of elongation factor‑2 resulting in cell death.[118,119] One‑third of patients demonstrated an objective response in phase I and II trials and 30% in phase III trials initiated for refractory/ advanced CTCL.[120] Combination therapy with denileukin diftitox and retinoids has been studied, as the latter causes the upregulation of the CD 25 and CD 122 subunits in IL 2R sensitizing to the effects of denileukin diftitox.[121] Doses of bexarotene greater than 150 mg/day were capable of upregulation of IL 2R and enhancing the efficacy of denileukin diftitox. Histone deacetylase (HDAC) inhibitors

Chromosomal deletions in 1p, 17p, 10q, and 19 and gains on chromosomes 4q, 18, and 17q are associated with more advanced forms of CTCLs. [122] In a study, DNA isolated from 28 patients of CTCL revealed 35 CpG hypermethylated islands in at least 4 patients.[123] Consequently, epigenetic modification emerged in the form of HDAC inhibitors, which prevent the removal of acetyl modification to lysine residues, leading to alterations in gene expression.[124] Recent data indicates that inhibiting HDAC activity can restore the normal transcription of genes by preventing the expression of STAT target genes, leading to differentiation and apoptosis.[125] Depsipeptide (Romidepsin) was the first drug of this class. Of the 27 patients administered a dose of 14 mg/m 2 on days 1, 8, and 15, 3 with SS had a complete remission (CR) and 5 had a partial remission (PR). [126] Thrombocytopenia, leucopenia, reversible ST‑T segment changes, and QT prolongation on electrocardiogram were the toxicities observed. Vorinostat (Zolinza, suberoylanilide hydroxamic acid), an oral HDAC inhibitor, was approved by Food and Drug Administration in 2006. Other novel inhibitors such as belinostat and LBH589 are showing a promising activity. Cytotoxic chemotherapy

These agents are used in non‑responsive, rapidly progressive, or aggressive disease. Gemcitabine, a pyrimidine antimetabolite, when administered on days 1, 8, and 15 at a 28‑day schedule at doses of 1000‑1200 mg/m2, showed a response rate of 70%.[127,128] Nucleoside analogs such as Indian Journal of Cancer | July–September 2014 | Volume 51 | Issue 3

Pandey, et al.: Cutaneous T‑cell lymphomas

pentostatin have ORR as high as 70%.[129‑135] Investigators at MD Anderson Cancer Centre reported an ORR of 56% for dose‑escalated pentostatin (3‑5 mg/m2/day for 3 days on a 21‑day schedule) in 42 patients with CTCL.[136] Fludarabine and cladribine have demonstrated an ORR of 16% in refractory patients.[137] Pegylated liposomal doxorubicin showed an ORR of 88%, a CR of 42%, and a 13‑month disease‑free survival.[138] Forodesine (BCX‑1777) is a purine nucleoside phosphorylase inhibitor that causes the accumulation of deoxyguanosine and dGTP and T‑lymphocyte apoptosis.[139] Arabinosylguanine (ARA‑G), a prodrug of deoxyguanosine, has shown disappointing results in a study.[140] Monoclonal antibodies

Zanolimumab is a completely humanized monoclonal antibody that targets the CD4 receptor on T lymphocytes. Out of 49 patients with CTCL, partial remission was observed in 44% when treated with a dose of 280 mg/week, which was increased to 560 mg/week in early‑stage patients and 980 mg/ week in patients with advanced disease.[141] SGN‑30, a chimeric monoclonal antibody, recognizes the CD30 antigen expressed on tumor cells in patients with Hodgkin’s disease and ALCL. In an ongoing phase 2 study, among the 6 patients, there was 1 CR, 1 PR, and 1 sustained remission.[142] Alemtuzumab is a humanized monoclonal antibody targeting the CD52 antigen, and it has been shown to be effective in refractory T‑cell lymphomas. In a study, response was seen in 6 of 10 patients, including 2 CR and 4 PR.[143] Vaccines

Anti‑idiotype vaccines are being prepared from skin lesions. Peptide mimotope vaccines of tumor‑associated T‑cell epitopes have been prepared. Vaccination with monocyte‑derived tumor cells showed a response in 5 of 10 refractory CTCL patients. Recombinant DNA vaccine containing the interferon gamma gene has led to response in 13 patients.[144] Hematopoietic stem cell transplantation

It is an effective treatment for many malignant hematologic disorders refractory to other treatment regimens. Disappointing results have been achieved with high‑dose chemotherapy and autologous stem cell transplantation. Allogenic transplantation leads to a graft‑versus‑tumor effect and long‑term remissions. It should be considered earlier in the disease course because the graft‑versus‑lymphoma effect may not be able to overcome the aggressive nature of disease in patients with large tumor burden. Prognosis, Overall Survival, and Risk of Disease Progression The T cell lymphoma survival rate varies according to the subtype of the lymphoma and the stage of the presentation. In mycosis fungoides, the most common type, the 5‑year survival rate can be as high as 97%, whereas for the most advanced stage of the disease, this survival rate drops to 41%. [145] Studies demonstrated that the median OS in patients with tumor, erythrodermic, and extracutaneous diseases was found to be 40, 48, and 13 months, respectively.[146,147] A retrospective analysis of 297 patients with MF and SS, undertaken to study long‑term outcomes Indian Journal of Cancer | July–September 2014 | Volume 51 | Issue 3

and identify clinical predictors of outcome in patients with advanced‑stage disease (ASD), showed that median OS for ASD was 5 years, with a 10‑year predicted OS of 32%. Age at initial diagnosis, tumor stage, and clinical stage were found to be significant predictors of outcome. Large‑cell transformation was considered to be a poor prognostic factor.[148] Recently, a large cohort study of 1502 patients of MF/SS evaluating the survival and clinical outcome showed that advanced skin (T) stage, the presence in peripheral blood of the tumor clone without Sézary cells (B0b), increased lactate dehydrogenase, and folliculotropic MF were independent predictors of poor survival and increased risk of disease progression (RDP); large‑cell transformation and tumor distribution were independent predictors of increased RDP only; and N, M, and B stages, age, male sex, and poikilodermatous MF were only significant for survival.[149] References 1. Girardi M, Heald PW, Wilson LD. The pathogenesis of mycosis fungoides. N Engl J Med 2004;350:1978‑88. 2. Swerdlow S, Campo E, Lee Harris N, Jaffe ES, Pileri SA, Stein H, et al. editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. (IARC WHO Classification of Tumours). London: Oxford Univ Pr; 2008. 3. Kansas GS. Selectins and their ligands: Current concepts and controversies. Blood 1996;88:3259‑87. 4. Ferenczi K, Fuhlbrigge RC, Pinkus J, Pinkus GS, Kupper TS. Increased CCR4 expression in cutaneous T cell lymphoma. J Invest Dermatol 2002;119:1405‑10. 5. Qin JZ, Nestle FO, Häffner A, Dummer R, Burg G, Döbbeling U. Cutaneous T cell lymphoma cells contain constitutive NFkB complexes. J Invest Derm 1997;108:225. 6. Qin JZ, Kamarashev J, Zhang CL, Dummer R, Burg G, Döbbeling U. Constitutive and interleukin‑7‑ and interleukin‑15‑stimulated DNA binding of STAT and novel factors in cutaneous T cell lymphoma cells. J Invest Dermatol 2001;117:583‑9. 7. Qin JZ, Zhang CL, Kamarashev J, Dummer R, Burg G, Döbbeling U. Interleukin‑7 and interleukin‑15 regulate the expression of the bcl‑2 and c‑myb genes in cutaneous T‑cell lymphoma cells. Blood 2001;98:2778‑83. 8. Qin JZ, Dummer R, Burg G, Döbbeling U. Constitutive and interleukin‑7/ interleukin‑15 stimulated DNA binding of Myc, Jun, and novel Myc‑like proteins in cutaneous T‑cell lymphoma cells. Blood 1999;93:260‑7. 9. Zhang C, Richon V, Ni X, Talpur R, Duvic M. Selective induction of apoptosis by histone deacetylase inhibitor SAHA in cutaneous T‑cell lymphoma cells: Relevance to mechanism of therapeutic action. J Invest Dermatol 2005;125:1045‑52. 10. Karenko L, Hahtola S, Päivinen S, Karhu R, Syrjä S, Kähkönen M, et al. Primary cutaneous T‑cell lymphomas show a deletion or translocation affecting NAV3, the human UNC‑53 homologue. Cancer Res 2005;65:8101‑10. 11. Greene MH, Dalager NA, Lamberg SI, Argyropoulos CE, Fraumeni JF Jr. Mycosis fungoides: Epidemiologic observations. Cancer Treat Rep 1979;63:597‑606. 12. Morales‑Suárez‑Varela MM, Olsen J, Johansen P, Kaerlev L, Guénel P, Arveux P, et al. Occupational risk factors for mycosis fungoides: A European multicenter case‑control study. J Occup Environ Med 2004;46:205‑11. 13. Abel EA. Mycosis fungoides and occupational exposures. Is there an association? Dermatol Clin 1990;8:169‑71. 14. Weinstock MA, Gardstein B. Twenty‑year trends in the reported incidence of mycosis fungoides and associated mortality. Am J Public Health 1999;89:1240‑4. 15. Ravat FE, Spittle MF, Russell‑Jones R. Primary cutaneous T‑cell lymphoma occurring after organ transplantation. J Am Acad Dermatol 2006;54:668‑75. 16. Jackow CM, Cather JC, Hearne V, Asano AT, Musser JM, Duvic M. Association of erythrodermic cutaneous T‑cell lymphoma, superantigen‑positive staphylococcus aureus, and oligoclonal T‑cell receptor V beta gene expansion. Blood 1997;89:32‑40. 17. Duvic M, Hester JP, Lemak NA. Photopheresis therapy for cutaneous T‑cell lymphoma. J Am Acad Dermatol 1996;35:573‑9. 299

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How to site this article: Pandey SS, Garg S, Dwivedi A, Tripathi R, Tripathi K, Bansal M. Cutaneous T-cell lymphomas and their management strategies. Indian J Cancer 2014;51:293-302. Source of Support: Nil, Conflict of Interest: None declared.

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