Clinical Practice Guidelines for Cutaneous Lymphomas

Abstract

Primary cutaneous lymphomas are non-Hodgkin lymphomas, which are broadly divided into cutaneous T-cell lymphomas and cutaneous B-cell lymphomas. These classifications include numerous distinct entities, all with varying clinical presentations and disease courses. Herein, we will review the cutaneous T-cell lymphomas, including Mycosis Fungoides, Sézary syndrome, CD30+ lymphoproliferative disorders, as well as other less common entities. Cutaneous B-cell lymphomas will also be discussed, including primary cutaneous marginal zone lymphoma, cutaneous folliclecenter lymphoma, diffuse large B-cell lymphoma, leg type, as well as other less common entities. Accurate and early diagnosis is key, as the treatment and prognosis varies significantly between conditions.

Introduction

Primary cutaneous lymphomas are defined as non-Hodgkin lymphomas that present in the skin without evidence of extracutaneous involvement at the time of diagnosis. The skin is the second most common site of involvement for non-Hodgkin lymphomas, and is characterized by an estimated annual incidence of 1:100,000.¹ Primary cutaneous lymphomas can be broadly divided into cutaneous T-cell lymphomas and cutaneous B-cell lymphomas. Clinical course and prognosis varies significantly between entities, thus proper diagnosis and classification is of the utmost importance. The objective of this article is to provide the primary care physician with an understanding of the clinical presentation, diagnosis, prognosis, and treatment of several primary cutaneous lymphomas and other lymphoproliferative disorders that often present in the skin.

Cutaneous T-cell Lymphomas

Cutaneous T-cell lymphomas comprise approximately 75–80% of all primary cutaneous lymphomas in the Western World.² Included in this classification are Mycosis Fungoides and its variants, Sézary syndrome, CD30+ lymphoproliferative disorders, and other more rare entities including subcutaneous panniculitis-like T-cell lymphoma, extranodal NK/T-cell lymphoma nasal type, primary cutaneous peripheral T-cell lymphoma not otherwise specified, and adult T-cell leukemia/lymphoma.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma and accounts for almost 50% of all primary cutaneous lymphomas.² Mycosis fungoides primarily affects middle age to older adults, with a recent study reporting a mean age at diagnosis of age 53.7, with a range of 8 to 91 years.³ Clinical presentation may be varied, with patients presenting with multiple hypopigmented to pink to hyperpigmented patches, plaques, or tumors, which may or may not ulcerate as the disease progresses. The tumor cells are typically CD3+, CD4+, and usually CD8−. There is often predilection for “bathing suit” or “double covered” distribution of lesions early on in the disease course. The disease follows an indolent course, with progression typically occurring over many years. In later stages of the disease, lymph nodes, hematologic, and other visceral organ involvement may occur. Prognosis depends on stage and extent of disease. For those patients with limited body surface area of patch or plaque stage lesions their life expectancy is unchanged from matched controls. Prognosis worsens in patients with extensive body surface area of involvement, those with tumor stage lesions, and as expected those with extracutaneous involvement.

Treatment is guided by stage and degree of body surface area involvement. (See www.cancer.gov/cancertopics/pdq/treatment/mycosisfungoides/HealthProfessional) Early stage MF (Stage IA–IIA) is managed with skin directed therapies, including topical corticosteroids and phototherapy.⁴ In cases unresponsive to the above, topical nitrogen mustard, bexarotene, local radiation, and PUVA are often employed.⁴ Treatment options for more advanced disease includes, total skin electron beam therapy, interferon therapy (IFNα and IFNγ), systemic bexarotene, extracorporeal photopheresis, biologic therapies including Alemtuzumab, a monoclonal antibody against surface antigen CD52, histone deacetylase inhibitors including vorinostat and romidepsin, as well as single and multiagent chemotherapy.⁴ Investigational therapies including lenalidomide, toll-like receptor agonists, interleukin-12 and interleukin-2, zanolimumab, a monoclonal antibody against CD4, proteasome inhibitor bortezomib, anti-PD1 agents, protein kinase C inhibitors, and phosphoinositide 3-kinase inhibitors.⁴ Variants of mycosis fungoides have been classified based on their own unique clinical and histopathologic features. Folliculotropic MF is characterized by lymphocytic infiltrates that are tropic to hair follicle structures with relative sparing of the epidermis and clinical lesions exhibiting predilection for the head and neck. Lesions are often folliculocentric papules or plaques/tumors, often with associated alopecia. Eyebrow involvement is especially characteristic. Prognosis is similar to patients with classic tumor stage MF, with disease specific five-year survival studied at 70–80%.² Treatment of this condition is often challenging, and skin directed therapies are often ineffective.² Pagetoid reticulosis is a variant of MF with very localized, slowly growing patches and plaques of intraepidermal neoplastic T-cells. Extracutaneous involvement and disease related deaths have never been reported in this condition, and treatment is focused on the individual lesions and typically includes radiotherapy, excision, topical steroids or topical nitrogen mustard.² Granulomatous slack skin is a rare subtype in which there is development of localized loose skin in areas of skin folds with a granulomatous infiltrate on histopathology. Clinical course is often indolent, and treatment with radiotherapy is suggested to be effective, although studies are limited.²

Sézary syndrome is an advanced stage cutaneous lymphoma classically consisting of erythroderma, lymphadenopathy, and circulating neoplastic T-cells. The International Society for Cutaneous Lymphomas (ISCL) recommends that for diagnosis, an absolute Sézary count of greater than 1000 cells/mm³, or presence of immunophenotypical abnormalities confirming a T-cell clonality in the peripheral blood, must be present.⁵ Clinically patients often present with erythroderma, and may or may not exhibit exfoliation, edema, alopecia, lymphadenopathy, hyperkeratosis of palms and soles, and/or pruritus.² Prognosis is often poor, with disease specific five-year survival noted to be 24%, with most patients dying of infections in the setting of immunosuppression.² Treatment strategies are similar to those of advanced stage mycosis fungoides including extracorporeal photopheresis, interferons, PUVA, oral retinoids such as bexarotene, anti-folates such as methotrexate, and biologic targeted therapies.⁴

Primary cutaneous CD30+ lymphoproliferative disorders are the second most common group of cutaneous T-cell lymphomas, and account for approximately 30% of cases.² Included in this classification is primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis. These entities share similar histopathologic features of a dense inflammatory infiltrate of CD30+ cells. Although some characteristic features on histopathology may aid in diagnosis, often times clinical history, disease course, and follow up are the main determinants of a final diagnosis. Primary cutaneous anaplastic large-cell lymphoma most often affects adults, with a male predominance.² Most lesions are solitary nodules or tumors that often ulcerate, however multiple lesions can occur in up to 20% of patients. The lesions may spontaneously regress but local recurrence is common and extracutaneous involvement may occur in up to 10% of patients.^{2, 6} Prognosis has been shown to be excellent in these patients with 5-and 10-year disease-related survival rates over 90%.⁶ Recommended treatment for solitary lesions is local radiotherapy or excision.⁶ Multiagent chemotherapy has been suggested for those with disseminated disease; however, local skin recurrence after treatment cessation is common and not necessarily associated with a more aggressive course.⁶ Lymphomatoid papulosis is a chronic, recurrent and self-limiting condition characterized by papules, papulonecrotic, or nodular lesions that characteristically regress with atrophic scarring in weeks to months, and frequently occur on the trunk and limbs.² The duration of the disease can last months to over 40 years.² In approximately 20% of patients, another lymphoma is diagnosed at some point, either before, during, or after the course of their disease.^{2, 6} Prognosis is excellent, with a recent study citing a 100% five- and ten-year disease related survival.⁶ Given that no treatment has been shown to be curative or to affect the natural course of the disease, the benefits of temporary improvement with active treatment must be balanced against the potential side effects of various treatment modalities.⁶ If few lesions are present, no active treatment may be necessary.⁶ When treatment is desired, in patients with many lesions or those in cosmetically sensitive areas, low dose methotrexate or PUVA are typically the treatments of choice with radiotherapy or excision as options for larger, localized lesions.⁶

Other entities included within the cutaneous T-cell lymphoma classification include subcutaneous panniculitis-like T-cell lymphoma, extranodal NK/T-cell lymphoma, nasal-type, adult T-cell lymphoma/leukemia, and primary cutaneous peripheral T-cell lymphoma, unspecified. Subcutaneous panniculitis T-cell lymphoma is characterized by an infiltrate of T-cells and macrophages in the subcutaneous tissue, and presents as nodules or deep subcutaneous plaques which may demonstrate ulceration, most often involving the extremities and trunk.⁷ This condition exhibits an α/β phenotype, and follows an indolent clinical course.⁷ A similar condition with a γ/δ phenotype, which exhibits an aggressive clinical course and poor prognosis, has since been designated under the category of peripheral T-cell lymphoma, unspecified.⁷ Hemophagocytic syndrome is an uncommon, but potentially fatal condition associated with this disease.⁷ Extranodal NK/T-cell lymphoma, nasal-type is an EBV+ associated lymphoma of NK-cells or T-cells that commonly occurs in the nasal cavity/oropharynx or skin, and often presents as lesions on the trunk and extremities or as a midline destructive facial lesion.² Systemic symptoms, extracutaneous involvement, and hemophagocytic syndrome may also be present.² This condition follows an aggressive clinical course, and systemic chemotherapy is the recommended treatment.² Adult T-cell leukemia/lymphoma is a T-cell neoplastic disorder associated with human T-cell leukemia virus 1 (HTLV-1) and most commonly occurs in regions with high prevalence of this virus.² Often patients present with the acute form of this condition, demonstrating leukemic involvement, lymphadenopathy, diffuse cutaneous lesions, and other systemic signs and symptoms.² In rare cases, smoldering forms of this condition have been reported with primarily limited skin involvement only.² Prognosis and treatment is dependent on the clinical subtype and degree of systemic involvement.² Primary cutaneous peripheral T-cell lymphoma, unspecified is an heterogeneous group of conditions that encompasses all other cutaneous T-cell neoplasms that do not fit into another defined category. Previously included in this group was primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, cutaneous gamma-delta T-cell lymphoma, and primary cutaneous small-medium CD4+ T-cell lymphoma; however these entities have recently been given their own distinct provisional classifications.

Cutaneous B-cell Lymphomas

Cutaneous B-cell lymphomas comprise approximately 25% of all cutaneous lymphomas and are divided into three main morphologic groups, primary cutaneous marginal zone lymphoma, cutaneous follicle-center lymphoma, and diffuse large B-cell lymphoma, leg type.² Less common entities included in this classification include diffuse large B-cell lymphoma, other type, and intravascular large B-cell lymphoma.²

Cutaneous marginal zone lymphoma is a lymphoma arising from cells of the marginal zone, including centrocytes, lymphoplasmacytoid cells, and plasma cells, as well as centroblasts, immunoblasts, and reactive T-cells.^2,8 Lesions are often red to violaceous, scattered papules, nodules, patches, or plaques often on the trunk and upper extremities. ^{2, 8} European cases have been reported in association with Borrelia burgdorferi; however, this has not been reported in cases elsewhere. ^{2, 8} Phenotypically cutaneous marginal zone lymphoma is classically bcl-2 positive and bcl-6 negative. This condition has an excellent prognosis, with five-year disease related survival noted to be >95%.^{2, 9} First line treatment of localized lesions includes radiotherapy and excision.⁹ For more wide spread lesions, close observation, radiotherapy for focal symptomatic lesions, systemic chemotherapy and/or the monoclonal antibody rituximab may be used.⁹ For those cases associated with Borrelia infection, treatment with antibiotics should be considered.⁹

Primary cutaneous follicle-center lymphoma is a lymphoma of cells of the follicle center, usually including a combination of centrocytes and centroblasts.² Clinically this condition often presents with solitary or grouped papules, nodules, or plaques, usually on the head or scalp and trunk.^{2, 8} Lesions typically enlarge locally, but extracutaneous disease is uncommon.² Phenotypically, the neoplastic follicle cells express bcl-6, and expression of bcl-2 is typically absent or faint.² Prognosis is again excellent, with five-year disease related survival noted to be over 95%.² Treatment is very similar to that of cutaneous marginal zone lymphoma, with surgical excision or radiotherapy being the recommended treatment for solitary lesions. ⁹ For more widespread involvement, rituximab is the first line therapy, however, in severe or refractory cases systemic chemotherapy may be considered.⁹

Primary cutaneous diffuse large B-cell lymphoma, leg type is neoplastic disorder of centroblasts and immunoblasts, which typically presents as a red to violaceous nodules or tumors on the lower extremities.² Phenotypically, bcl-2 and bcl-6 are often expressed, as is MUM-1. Extracutaneous disease is common, with these tumors having a relatively high propensity to disseminate.¹⁰ Prognosis is variable with disease related 5-year survival being 40–50% in patients with multiple lesions at time of diagnosis, to 100% in those patients that present with a single lesion. ^{2, 10} Given the propensity of this lymphoma to disseminate, and its clinical course being similar to that of systemic diffuse large b-cell lymphoma, it is recommended that first line treatment be multi-agent CHOP chemotherapy, with or without rituximab.⁹ In those patients where systemic chemotherapy is not an option, radiotherapy to individual lesions or rituximab alone can be considered.⁹ Other, rare large B-cell lymphomas can also present in the skin. For those cases that do not fit into another previously mentioned category, the term primary cutaneous diffuse large B-cell lymphoma, other, has been designated. Included in this classification are morphologic variants of diffuse large B-cell lymphoma including anaplastic or plasmablastic subtypes and T-cell/histiocyte rich large B-cell lymphoma.² The presentation of these particular lymphomas on the skin is often a manifestation of systemic disease.² Intravascular large B-cell lymphoma is a subtype in which neoplastic B-cells have accumulated within blood vessels and often affect many organ systems, however rarely cutaneous disease only can occur.²

Plasmacytoid/Dendritic Cell Neoplasms

Not included in any of the above classifications is an entity known as blastic plasmacytoid dendritic cell neoplasm, an aggressive neoplastic process of plasmacytoid origin. This condition exhibits frequent leukemic, lymph node, and bone marrow involvement with an extremely high propensity for cutaneous lesions, which may be the presenting finding.¹¹ Skin lesions are often asymptomatic, with variable morphology from papules, nodules, and plaques to bruise-like lesions that may be solitary or multiple.¹¹ Phenotypically these lesions are positive for CD4 and CD56. This condition offers a poor prognosis, with a median 5-year survival to be noted at 12–14 months. ^{2, 11} Systemic, multi-agent, chemotherapy is often attempted for treatment, however relapse is quite common.¹¹

Conclusions/Recommendations

In summary, cutaneous lymphomas are a heterogenous group of disorders with variable presentations, which can often pose a diagnostic conundrum to clinicians. A multidisciplinary approach is recommended, and communication between primary care physicians, dermatologists, dermatopathologists, and oncologists is essential for accurate and early diagnosis.

Biography

Angela M. Sutton, DO, is a Resident at Saint Louis University Department of Dermatology. M. Yadira Hurley, MD, (above), is an Associate Professor of Dermatology and Pathology at the Saint Louis University School of Medicine.

Contact: hurleyy@slu.edu