Section 2 -

Spectrum of Cutaneous CD30-Positive Lymphoproliferative Disorders Rein Willemze & C.J.L.M. Meijer

Primary cutaneous CD30-positive lymphoproliferative disorders (LPD) represent the second most common group of CTCL, accounting for approximately 25% of CTCL. This group includes primary cutaneous anaplastic large cell lymphoma (C-ALCL), lymphomatoid papulosis (LyP), and borderline cases [1, 2, 3]. C-ALCL and LyP have over­lapping clinical, histological and immunophe­notypical features and form a spectrum of disease [3]. Since histologic criteria alone are often insufficient to differentiate between these two ends of the spectrum, the clinical appearance and course are used as decisive criteria for thedefinite diagnosis and choice of treat­ment. The term "borderline case" refers to cases, in which, despite careful clinicopathologic correlation, a definite distinction between C-ALCL and LyP cannot be made. Clinical examination during follow-up will generally disclose if the patient has C-ALCL or LyP [4]. These primary cutaneous CD30-positive LPD should be differentiated from: skin localizations of systemic ALCL cases of MF with transformation into a CD30-positive large cell lymphoma other well-defined types of CTCL, which may sometimes express the CD30 antigen. reactive skin conditions harbouring large CD30+ activated T-cells, such as several viral infections, arthropod reactions, scabies and so on. Primary Cutaneous Anaplastic Large Cell Lymphoma C-ALCL is composed of large cells with an anaplastic, pleomorphic or immunoblastic cytomorphology and expression of the CD30 antigen by the majority (more than 75%) of tumor cells. There is no clinical evidence or history of LyP, MF or another type of CTCL. Clinical Features C-ALCL predominantly affect adults, and are rare in children or adolescents. Most patients present with solitary or localized nodules or tumors that often develop ulceration. Multifocal lesions are seen in about 20% of the patients. The skin lesions may show partial or complete spontaneous regression, as in LyP. These lymphomas frequently relapse in the skin. Extracutaneous dissemination occurs in approximately 10% of the patients, and mainly involves the regional lymph nodes. The prognosis is usually favorable with a 10-year disease-related survival exceeding 85% [4, 5]. Pathology C-ALCL show diffuse infiltrates with cohesive sheets of large CD30+ tumor cells. In most cases the tumor cells have the characteristic morphology of anaplastic cells, with round, oval or irregularly shaped nuclei, prominent (eosinophilic) nucleoli and abundant cytoplasm. Less commonly (20–25%), they have a pleomorphic or immunoblastic appearance. Reactive lymphocytes are often present at the periphery of the tumor. Ulcerating lesions may show a LyP-like histology with an abundant inflammatory infiltrate of reactive T cells, histiocytes, eosinophils, neutrophils, and few CD30+ cells. In such cases epidermal hyperplasia may be prominent. Immunophenotype The neoplastic cells often express a CD4+ T-cell phenotype with variable loss of CD2, CD5 and/or CD3. Some cases (<5%) have a CD8+ T-cell phenotype. CD30 must be expressed by the majority of neoplastic cells. Expression of cytotoxic proteins (granzyme B, TIA-1, perforin) is noted in approximately 70% of the cases. Unlike systemic ALCL, most C-ALCL express the cutaneous lymphocyte antigen (CLA), but do not express EMA and ALK (anaplastic lymphoma kinase), indicative of the t(2;5) chromosomal translocation [6]. Staining for CD15 is generally negative. Coexpression of CD56 is observed in rare cases, but does not appear to be associated with an unfavorable prognosis [7]. Genetic Features The t(2;5) translocation, which is predominantly found in systemic ALCL in children, is not or rarely found in C-ALCL [6]. Treatment Solitary lesions can be treated with local radiotherapy or surgical excision. Patients presenting with multifocal skin lesions should be treated with radiotherapy (if there are only a few lesions) or with low-dose methotrexate as in LyP [4, 8]. Patients presenting with or developing extracutaneous disease or rare patients with rapidly progressive skin disease should be treated with doxorubicin-based multiagent chemotherapy. Lymphomatoid Papulosis Lymphomatoid papulosis (LyP) is defined as a chronic, recurrent, self-healing papulonecrotic or papulonodular skin disease with histologic features suggestive of a (CD30-positive) malignant lymphoma. Clinical Features LyP usually presents in adults, but may occur in children as well. The typical skin lesions in LyP are red–brown papules and nodules that may develop central hemorrhage, necrosis and crusting, and subsequently spontaneously disappear within 3 to 12 weeks, and may leave superficial atrophic scars. The predominant sites of involvement are the trunk and limbs. The duration of the disease may vary from several months to more than 40 years. In up to 20% of patients LyP may be preceded by, associated with, or followed by, another type of malignant (cutaneous) lymphoma, generally MF, a C-ALCL or Hodgkin's disease. However, the prognosis is usually excellent. In a recent study of 118 patients with LyP only five patients (4%) developed a systemic lymphoma, and only two patients (2%) died of systemic disease over a median follow-up period of 77 months [4]. Genetic Features Clonally rearranged T-cell receptor genes have been detected in 60-70% of LyP lesions. Identical rearrangements have been demonstrated in LyP lesions and associated lymphomas [9]. The t(2;5)(p23;q35) translocation is not or rarely found in LyP [6]. Pathology The histologic picture of LyP is extremely variable, which in part correlates with the age of the sampled skin lesion. Characteristically, fully developed lesions show a wedge-shaped, initially non-epidermotropic, infiltrate with scattered or small clusters of large atypical, sometimes multinucleated or Reed–Sternberg-like, CD30-positive T cells, interspersed in an extensive inflammatory infiltrate composed of small lymphocytes, neutrophils and/or eosinophils. These large CD30-positive cells, which have the morphological and immunophenotypical characteristics of the neoplastic cells in C-ALCL, are relatively few in early lesions, more numerous in fully developed lesions, but may be completely absent in resolving lesions. The presence of scattered neutrophils within a moderately acanthotic and parakeratotic, but otherwise unaffected epidermis is a characteristic finding. In rare cases the skin lesions demonstrate a monotonous population or large clusters of large CD30-positive T cells with relatively few admixed inflammatory cells, a histologic appearance typically found in C-ALCL [3]. Treatment Since a curative therapy is not available and none of the available treatment modalities affects the natural course of the disease, the short-term benefits of active treatment should be balanced carefully against the potential side effects [4]. In patients with relatively few non-scarring lesions, active treatment is not necessary. In the case of cosmetically disturbing lesions (e.g. scarring or many papulonodules), low-dose oral methotrexate (5–20mg/week) is the most effective therapy for reducing the number of skin lesions [8]. Because of the potential risk for developing a systemic lymphoma, long-term follow-up is required in all patients with LyP. References Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-3785. Burg G, Jaffe ES, Kempf W, et al. WHO-EORTC classification for cutaneous lymphomas. In: LeBoit Ph, Burg G, Weedon D, Sarasin A (eds). World Health Organization Classification of Tumours. Pathology and Genetics of Skin Tumours. IARC Press: Lyon, 2001. Willemze R, Beljaards RC. Spectrum of primary cutaneous CD30+ lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol. 1993;28:973–80. Bekkenk M, Geelen FAMJ, van Voorst Vader PC, et al. Primary and secondary cutaneous CD30-positive lymphoproliferative disorders: long term follow-up data of 219 patients and guidelines for diagnosis and treatment. A report from the Dutch Cutaneous Lymphoma Group. Blood. 2000;95:3653–61. Liu HL, Hoppe RT, Kohler S, Harvell JD, Reddy S, Kim YH. CD30+ cutaneous lymphoproliferative disorders: The Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol. 2003;49:1049-58. DeCouteau JF, Butmarc JR, Kinney MC, Kadin ME. The t(2;5) chromosomal translocation is not a common feature of primary cutaneous CD30+ lymphoproliferative disorders: comparison with anaplastic large cell lymphoma of nodal origin. Blood. 1996;87:3437–41. Bekkenk MW, Kluin PM, Jansen PM, et al. Lymphomatoid papulosis with a NK-cell phenotype. Br J Dermatol 2001;145:318-322. Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Am Acad Dermatol. 1996;34:470–80. Kadin ME. Pathobiology of CD30+ cutaneous T-cell lymphomas. J Cut Pathol 2006;33 (Suppl.1):10-17.