Section 5 -

Primary Cutaneous T-cell & NK-Cell Lymphomas Elaine S. Jaffe M.D. National Cancer Institute Bethesda, MD

Classification of T-cell and NK-cell Lymphomas PTLs show great morphological diversity, and a spectrum of histological appearances can be seen within individual disease entities. The cellular composition can range from small cells with minimal atypia to large cells with anaplastic features. In a similar vein, immunophenotypic markers have been less useful in classification T-cell lymphomas than B-cell lymphomas, as often one marker is shared by multiple disease entities. As an example, CD30, a hallmark of ALCL, is found in diverse lymphoid malignancies of T- and B-cell types. Finally, the molecular pathogenesis for most T-cell lymphomas is as yet undiscovered. For the above reasons, clinical features have played a major role in defining many of the specific entities included in the WHO classification. [1] Cutaneous lymphomas are no exception, and many lymphomas presenting in the skin appear to have distinctive clinical and biological features. Mycosis Fungoides and Sezary Syndrome Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma. There is a 2:1 male predilection, with a median age of 55 at diagnosis and increasing frequency for older patients. The incidence in the general population is 4 per million, with approximately 1,500 new cases and 500 deaths a year in the United States. Erythematous, hyperpigmented or hypopigmented patches or plaques that typically have a "bathing trunk" distribution characterize early-stage MF. Tumors are seen in late or advanced disease, but rarely at presentation. It is likely that most instances of so-called mycosis fungoides d'emblee in the literature actually represented other forms of cutaneous lymphoma. The term is rarely if ever used currently. Erythroderma is a feature of Sezary syndrome (SS), and is associated with a leukemic phase. The term cutaneous T-cell lymphoma or CTCL is ambiguous, and probably best avoided as a diagnosis. In some circumstances it has been used to encompass both MF and SS; in other circumstances it has been used to describe any cutaneous T-cell lymphoma. Primary Cutaneous Anaplastic Large Cell Lymphoma CD30-TLPD is a spectrum of conditions ranging from lymphomatoid papulosis (LYP) to primary cutaneous ALCL (C-ALCL). [2] A common feature in all is a CD30-positive, CD4-positive T-cell, which in C-ALCL can be shown to be clonal. In LYP the atypical cells are in the minority and are associated with a marked inflammatory background. Lesions regress spontaneously, and dissemination never occurs. C-ALCL lies at the opposite end of the spectrum; large atypical CD30-positive cells predominate, regression often occurs without therapy, and spread to lymph nodes may be seen. [3] However, widespread disease is relatively rare. C-ALCL is consistently negative for the ALCL-associated tyrosine kinase (ALK) although systemic ALCL may present with cutaneous disease. In fact, the skin is one of the more common sites of involvement for systemic ALCL. Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) SPTCL usually presents with multiple subcutaneous nodules of varying size, primarily affecting the extremities. [4, 5, 6] It shows a broad age distribution and an equal male: female ratio. The neoplastic cells are generally confined to subcutaneous tissue, and frequently infiltrate individual fat cells with a rim-like arrangement at the cell border, which is a helpful feature in the differential diagnosis with benign panniculitis. Dermal and epidermal involvement are generally absent, a feature which helps to distinguish SPTCL from muco-cutaneous gd TCL involving subcutaneous tissue. [7] Panniculitis-like features may be seen in both, but SPTCL has a better prognosis. In the latest iteration of the WHO classification, published jointly with the EORTC, SPTCL is limited to a cytotoxic tumor of ab T-cell derivation. [8] The neoplastic cells express an activated ab CD8+ cytotoxic T-cell phenotype. In addition, the cells are positive for the cytotoxic associated proteins, granzyme B, perforin and TIA- 1. These proteins mediate cytotoxicity and apoptosis by T-cells and NK-cells, and therefore may be responsible for the cellular destruction characteristic of these lesions. Primary cutaneous gamma delta T-cell lymphomas gd T-cells comprise fewer than 5% of all normal T-cells, and show a restricted distribution, being found mainly in the splenic red pulp, intestinal epithelium, and other epithelial sites. It is notable that these sites are more commonly affected by gd T-cell lymphomas, which otherwise are relatively rare. [7, 9] Gamma-delta T-cells are not MHC restricted in their function, and represent a first line of defense against bacterial peptides, such as heat shock proteins. [10] They are often involved in responses to mycobacterial infections, and both mucosal and cutaneous immunity. There are two main forms of gd TCL: the hepatosplenic form which never involves the skin and mucocutaneous gd TCL which commonly present in the skin and less frequently other mucosal sites. Cutaneous gd T-cell lymphomas exhibit subcutaneous, dermal, and even epidermal infiltration, in contrast to the restricted subcutaneous involvement of SPTCL. [5, 6, 11, 12] Cutaneous gd T-cell lymphomas also have a worse prognosis than SPTCL. [7] Peripheral T-cell lymphomas, unspecified This category is a diagnosis of exclusion. Such cases can present in the skin. Most are negative for CD30 and have an aggressive clinical course. A minor subset of cases presenting with localized disease, positivity for CD4, and an indolent clinical course has been identified provisionally by studies conducted by the EORTC. [13] T-cell Lymphomas with a High Incidence of Secondary Cutaneous Involvement Extranodal NK/T-cell Lymphoma, Nasal and Nasal Type Extranodal NK/T-cell lymphoma, nasal type is a distinct clinicopathologic entity highly associated with EBV. [14] It is more common in Asia than in Europe and the U.S. The term nasal-type is derived from the fact that the midline nasal and facial structures are the most common site of origin for this tumor. [15, 16] Additionally, adjoining tissues such as the paranasal sinuses, oral cavity, palate, and orbit may be involved. Dissemination of disease to other extranodal sites is common. Skin is one of the most common secondary sites of involvement. The cutaneous infiltrates usually do not involve the epidermis, often presenting with tumors or plaques. Necrosis is common. The tumor cells usually express CD2, CD56, and cytoplasmic CD3e. Cytotoxic molecules (TIA1, granzyme B, perforin) are positive in most cases. Other T and NK-cell associated antigens as CD4, CD5, CD8, TCRß, TCR d, CD16 and CD57 are negative. Hydroa vacciniforme-like lymphoma, a form of EBV-positive T-cell or NK-cell lymphoma seen mainly in children. [17] It presents mainly with cutaneous involvement, and in some patients the skin lesions appear to be precipitated by a reaction to insect bites. Adult T-cell Lymphoma/Leukemia (HTLV-1+) Adult T-cell lymphoma/leukemia (ATLL) is a clinicopathologic entity caused by the retrovirus HTLV-1. [18] HTLV-1 is endemic in the Caribbean basin and Southwestern Japan. [19] Skin involvement is relatively common in ATL, and is seen in one-half to two-thirds of patients at presentation. Skin lesions consist of plaques, papules, tumors or an exfoliative erythroderma. [20, 21] Histologically, skin lesions in ATLL can be impossible to distinguish from mycosis fungoides, and it has been proposed by some that a related or defective retrovirus might be found in mycosis fungoides. Smoldering and chronic ATLL have a more indolent clinical course, with a longer median survival. [22] These forms are associated with skin rash, but minimal or absent lymphadenopathy and hepatosplenomegaly. [23] References: Jaffe ES, Harris NL, Stein H, Vardiman J. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001. Willemze R, Beljaards RC. Spectrum of primary cutaneous CD30 (Ki-1)-positive lymphoproliferative disorders. A proposal for classification and guidelines for management and treatment. J Am Acad Dermatol 1993;28(6):973-80. Paulli M, Berti E, Rosso R, et al. CD30/Ki-1-positive lymphoproliferative disorders of the skin--clinicopathologic correlation and statistical analysis of 86 cases: a multicentric study from the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group. J Clin Oncol 1995;13(6):1343-54. Gonzalez CL, Medeiros LJ, Braziel RM, Jaffe ES. T-cell lymphoma involving subcutaneous tissue: a clinicopathologic entity commonly associated with hemophagocytic syndrome. Am J Surg Pathol 1991;15:17-27. Salhany KE, Macon WR, Choi JK, et al. Subcutaneous panniculitis-like T-cell lymphoma: clinicopathologic, immunophenotypic, and genotypic analysis of alpha/beta and gamma/delta subtypes. Am J Surg Pathol 1998;22(7):881-93. Kumar S, Krenacs L, Elenitoba-Johnson K, et al. Subcutaneous panniculitic T-cell lymphoma is a tumor of cytotoxic T-lymphocytes. Hum Pathol 1998;29:397-403. Toro JR, Liewehr DJ, Pabby N, et al. Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma. Blood 2003;101(9):3407-12. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105(10):3768-85. Belhadj K, Reyes F, Farcet JP, et al. Hepatosplenic {gamma}{delta} T-cell lymphoma is a rare clinicopathologic entity with poor outcome: report on a series of 21 patients. Blood 2003;102(13):4261-9. Delves PJ, Roitt IM. The Immune System. First of two parts. N Engl J Med 2000;343:37-49. Toro JR, Beaty M, Sorbara L, et al. Gamma delta T-cell lymphoma of the skin: a clinical, microscopic, and molecular study. Archives of Dermatology 2000;136(8):1024-32. Berti E, Cerri A, Cavicchini S, et al. Primary cutaneous gamma/delta T-cell lymphoma presenting as disseminated pagetoid reticulosis. J Invest Dermatol 1991;96:718-23. Bekkenk MW, Vermeer MH, Jansen PM, et al. Peripheral T-cell lymphomas unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients. Blood 2003;102(6):2213-9. Jaffe ES, Chan JKC, Su IJ, et al. Report of the workshop on nasal and related extranodal angiocentric T/NK cell lymphomas: definitions, differential diagnosis, and epidemiology. Am J Surg Pathol 1996;20(1):103-11. Ng SB, Lai KW, Murugaya S, et al. Nasal-type extranodal natural killer/T-cell lymphomas: a clinicopathologic and genotypic study of 42 cases in Singapore. Mod Pathol 2004. Cheung MM, Chan JK, Wong KF. Natural killer cell neoplasms: a distinctive group of highly aggressive lymphomas/leukemias. Semin Hematol 2003;40(3):221-32. Zhang Y, Nagata H, Ikeuchi T, et al. Common cytological and cytogenetic features of Epstein-Barr virus (EBV)-positive natural killer (NK) cells and cell lines derived from patients with nasal T/NK-cell lymphomas, chronic active EBV infection and hydroa vacciniforme-like eruptions. British Journal of Haematology 2003;121(5):805-14. Takatsuki K, Matsuoka M, Yamaguchi K. Adult T-cell leukemia in Japan. J Acquir Immune Defic Syndr Hum Retrovirol 1996;13 Suppl 1:S15-9. Jaffe ES, Blattner WA, Blayney DW, et al. The pathologic spectrum of adult T-cell leukemia/lymphoma in the United States. Am J Surg Pathol 1984;8:263-75. Tobinai K, Watanabe T, Jaffe ES. Human T-cell leukemia virus type I-associated adult T-cell leukemia-lymphoma. In: Mauch PM, Armitage JO, Coiffier B, Dalla-Favera R, Harris NL, eds. Non-Hodgkin's Lymphoma. Philadelphia, PA: Lippincott, Williams, and Wilkins; 2004:295-306. Whittaker SJ, Ng YL, Rustin M, Levene G, McGibbon DH, Smith NP. HTLV-1-associated cutaneous disease: a clinicopathological and molecular study of patients from the U.K. Br J Dermatol 1993;128(5):483-92. Kawano F, Yamaguchi K, Nishimura H, Tsuda H, Takatsuki K. Variation in the clinical courses of adult T-cell leukemia. Cancer 1985;55(4):851-6. Shimoyama M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87). Br J Haematol 1991;79(3):428-37.