Clinically and biologically, cutaneous T-cell lymphomas (CTCL) represent a heterogeneous group of non-Hodgkin's lymphomas (NHL) defined by clonal proliferation of skin-homing malignant T lymphocytes. The spectrum of CD30+ cutaneous lymphoproliferative disorders includes lymphomatoid papulosis (LyP), cutaneous anaplastic large-cell lymphoma (CALCL), and borderline cases that represent the second most common types of CTCL after mycosis fungoides (MF) and comprise approximately 25% of all CTCL. Their common phenotypic hallmark is the CD30 antigen, a cytokine receptor belonging to the tumor necrosis factor receptor superfamily. Other overlapping features include common spontaneous regression of the skin lesions and in general a low-grade malignant course with an excellent prognosis.[2,3]
Clinical Manifestation and Differential Diagnosis
First described in 1956 by Dupont et al as histiomonocytic reticulosis and later coined by Macaulay in 1968, LyP has been recognized as a clinically benign but often recurrent skin condition. The skin of patients is characterized by the presence of a self-healing skin eruption of erythematous papules and nodules that may become hemorrhagic, necrotic, and/or ulcerative (Figure 1).[4,5] Clinically, lesions vary from papules and nodules to, less commonly, larger plaques, and follicular, vesicular, and pustular types. Oral involvement has been rarely observed. While individual lesions take weeks to several months to resolve, the disease may recur for decades and is highly variable. Arthropod bites, pityriasis lichenoides et varioliformis acuta (PLEVA), prurigo nodularis, folliculitis, and various cutaneous lymphomas may clinically resemble LyP.
LyP was previously considered a benign inflammatory process comprising a spectrum with pityriasis lichenoides. Both conditions are associated with crops of papules on the trunk and extremities that tend to ulcerate. However, LyP is now regarded as an indolent cutaneous lymphoma according to the new World Health Organization—European Organisation for Research and Treatment of Cancer (WHO-EORTC) classification.
Three histologic types have been identified, characterized as type A, B, and C (Table 1). Types A and C consist of large atypical lymphocytes resembling Reed-Sternberg cells. Type A cells are embedded in a dense inflammatory background with histiocytes, neutrophils, and eosinophils, and can resemble Hodgkin's disease, whereas type C cells are characterized by sheets of similar large atypical lymphocytes with prominent lavender nucleoli and open chromatin with fewer interspersed inflammatory cells (Figure 2). Only a few inflammatory cells are present. Type B simulates classical MF features, with epidermotropism and a dermal band-like infiltrate composed of small to medium-sized cells. It may represent an early stage in the evolution of the more conventional type A presentation.
Atypical cells exhibit a CD4+ CD8- CD30+ T-helper phenotype and frequently express cytotoxic proteins such as granzyme B, TIA-1, and perforin. Aberrant phenotypes with loss of the CD7 antigen frequently occur. The expression of CD15, a marker for Hodgkin and Reed-Sternberg cells, has been reported, but 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.[9,10] Pseudocarcinomatous epidermal hyperplasia was found in cases of LyP and CD30+ CALCL possibly associated with epidermal growth factor dysregulation (Figure 3). Recently published immunohistochemical data suggest that fascin expression in LyP may become a predictive marker for development of a second lymphoid malignancy. Low (or loss of) CD134 expression may also predict disease progression.
Cutaneous CD30+ Anaplastic Large-Cell Lymphoma
In 1985, Stein et al described a large-cell lymphoma defined by cohesive sheets of large lymphoid cells expressing the Ki-1 (CD30) antigen. This has led to the further recognition of CD30 expression as a common phenotypic hallmark for LyP and CD30+ CALCL. Most cases of CD30+ CALCL present as solitary or regional nodules and/or tumors that often show ulceration (Figure 4). The skin lesions may undergo spontaneous regression as in LyP, but often persist. Generalized or multifocal lesions are seen in about 20% of patients. Papules and plaques simulating morphea or ulcerated lesions resembling pyoderma gangrenosum have also been described. Extracutaneous or regional lymph node involvement is seen in 10% of patients at presentation.
CD30+ CALCL shows histologic and immunophenotypic overlap with LyP and may be difficult to distinguish at times. Therefore, clinical features are important in distinguishing CD30+ CALCL from LyP. A morphologic and immunophenotypic overlap with classic Hodgkin's disease has also been recognized. Histology shows a diffuse, nonepidermotropic infiltrate with cohesive proliferations of large CD30+ lymphocytes. In most cases, neoplastic cells show anaplastic features; less commonly, they have a pleomorphic or immunoblastic appearance (Figure 5). However, there is no difference in the prognosis and survival rate.
According to the WHO-EORTC system, CALCL is classified by the expression of CD30 in more than 75% of large atypical cells. However, it may show a wide morphologic spectrum including neutrophil-rich tumors. The atypical cells generally show an activated CD4+ T-helper cell phenotype with variable loss of T-cell markers and frequent expression of cytotoxic proteins. A CD8+ T-cell phenotype as well as coexpression of CD56 and CD30 have rarely been reported. The overlying epidermis may show a variable degree of pseudoepitheliomatous hyperplasia mimicking squamous cell carcinoma, thereby leading to inappropriate diagnosis and treatment (Figure 4).
In contrast to systemic anaplastic large-cell lymphoma (ALCL), primary CD30+ CALCL rarely carries the t(2;5) translocation and is usually ALCL kinase protein (ALK)-negative.[16,17] Clusterin was found to be a specific marker for ALCL, but it does not differentiate primary from secondary cutaneous ALCL, as the presence of the ALK protein apparently does. Epithelial membrane antigen (EMA) and expression of c-kit receptor (CD117) is usually negative in cases of CD30+ CALCL and LyP.
Borderline cases refer to those in which a difference between the clinical and histologic appearance exists. These include cases with the clinical presentation of a CD30+ CALCL but histologic features suggestive of LyP, and, conversely, cases with a recurrent, self-healing skin eruption that shows histologic features characteristic of a CD30+ CALCL. The distinction between LyP and CD30+ CALCL is not always possible based on histologic criteria. LyP type C has been described as a borderline lesion of CD30+ CALCL. Thus, the clinical appearance and the clinical course over time are used as decisive criteria for the definitive diagnosis and choice of treatment.
The presentation of CD30+ lymphoproliferative diseases can be a diagnostic challenge, as CD30 expression has been observed in cutaneous infiltrates of various reactive inflammatory and neoplastic diseases such as arthropod bites, scabies, PLEVA, Langerhans cell histiocytosis, cutaneous B-cell lymphomas with immunoblastic or large-cell features, and CD30+ large-cell transformation of MF. Therefore, clinicopathologic correlation is mandatory to establish a diagnosis and to avoid inadequate or excessive therapy.[8,20,21]
1. Willemze R, Jaffe ES, Burg G, et al: WHO-EORTC classification for cutaneous lymphomas. Blood 105:3768-3785, 2005.
2. 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 13:1343-1354, 1995.
3. Bekkenk MW, Geelen FA, van Voorst Vader PC, et al: Primary and secondary cutaneous CD30(+) lymphoproliferative disorders: A report from the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of 219 patients and guidelines for diagnosis and treatment. Blood 95:3653-3661, 2000.
4. Brosens, Dupont A, Thulliez A: [Histio-monocytic reticulosis and mycosis fungoides; four case reports.]. Arch Belg Dermatol Syphiligr 12:263-272, 1956.
5. Macaulay WL: Lymphomatoid papulosis. A continuing self-healing eruption, clinically benign-histologically malignant. Arch Dermatol 97:23-30, 1968.
6. Kempf W: CD30+ lymphoproliferative disorders: histopathology, differential diagnosis, new variants, and simulators. J Cutan Pathol 33(suppl 1):58-70, 2006.
7. Pujol RM, Muret MP, Bergua P, et al: Oral involvement in lymphomatoid papulosis. Report of two cases and review of the literature. Dermatology 210:53-57, 2005.
8. Cerroni L: Lymphomatoid papulosis, pityriasis lichenoides et varioliformis acuta, and anaplastic large-cell (Ki-1+) lymphoma. J Am Acad Dermatol 37:287, 1997.
9. Harvell J, Vaseghi M, Natkunam Y, et al: Large atypical cells of lymphomatoid papulosis are CD56-negative: A study of 18 cases. J Cutan Pathol 29:88-92, 2002.
10. Flann S, Orchard GE, Wain EM, et al: Three cases of lymphomatoid papulosis with a CD56+ immunophenotype. J Am Acad Dermatol 55:903-906, 2006.
11. Scarisbrick JJ, Calonje E, Orchard G, et al: Pseudocarcinomatous change in lymphomatoid papulosis and primary cutaneous CD30+ lymphoma: A clinicopathologic and immunohistochemical study of 6 patients. J Am Acad Dermatol 44:239-247, 2001.
12. Kempf W, Levi E, Kamarashev J, et al: Fascin expression in CD30-positive cutaneous lymphoproliferative disorders. J Cutan Pathol 29:295-300, 2002.
13. Gniadecki R, Rossen K: Expression of T-cell activation marker CD134 (OX40) in lymphomatoid papulosis. Br J Dermatol 148:885-891, 2003.
14. Burg G, Kempf W, Kazakov DV, et al: Pyogenic lymphoma of the skin: A peculiar variant of primary cutaneous neutrophil-rich CD30+ anaplastic large-cell lymphoma. Clinicopathological study of four cases and review of the literature. Br J Dermatol 148:580-586, 2003.
15. Boudova L, Kazakov DV, Jindra P, et al: Primary cutaneous histiocyte and neutrophil-rich CD30+ and CD56+ anaplastic large-cell lymphoma with prominent angioinvasion and nerve involvement in the forehead and scalp of an immunocompetent woman. J Cutan Pathol 33:584-589, 2006.
16. Herbst H, Sander C, Tronnier M, et al: Absence of anaplastic lymphoma kinase (ALK) and Epstein-Barr virus gene products in primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis. Br J Dermatol 137:680-686, 1997.
17. Sasaki K, Sugaya M, Fujita H, et al: A case of primary cutaneous anaplastic large cell lymphoma with variant anaplastic lymphoma kinase translocation. Br J Dermatol 150:1202-1207, 2004.
18. Lae ME, Ahmed I, Macon WR: Clusterin is widely expressed in systemic anaplastic large cell lymphoma but fails to differentiate primary from secondary cutaneous anaplastic large cell lymphoma. Am J Clin Pathol 118:773-779, 2002.
19. Rassidakis GZ, Georgakis GV, Oyarzo M, et al: Lack of c-kit (CD117) expression in CD30+ lymphomas and lymphomatoid papulosis. Mod Pathol 17:946-953, 2004.
20. Panhans A, Bodemer C, Macinthyre E, et al: Pityriasis lichenoides of childhood with atypical CD30-positive cells and clonal T-cell receptor gene rearrangements. J Am Acad Dermatol 35:489-490, 1996.
21. Laube S, Shah F, Marsden J: Consequences of misdiagnosis of lymphomatoid papulosis. Eur J Cancer Care (Engl) 15:194-198, 2006.
22. Wang HH, Lach L, Kadin ME: Epidemiology of lymphomatoid papulosis. Cancer 70:2951-2957, 1992.
23. Nijsten T, Curiel-Lewandrowski C, Kadin ME: Lymphomatoid papulosis in children: A retrospective cohort study of 35 cases. Arch Dermatol 140:306-312, 2004.
24. Wang HH, Myers T, Lach LJ, et al: Increased risk of lymphoid and nonlymphoid malignancies in patients with lymphomatoid papulosis. Cancer 86:1240-1245, 1999.
25. Sangueza OP, Galloway J, Eagan PA, et al: Absence of Epstein-Barr virus in lymphomatoid papulosis. An immunohistochemical and in situ hybridization study. Arch Dermatol 132:279-282, 1996.
26. Jang KA, Choi JC, Choi JH: Expression of cutaneous lymphocyte-associated antigen and TIA-1 by lymphocytes in pityriasis lichenoides et varioliformis acuta and lymphomatoid papulosis: Immunohistochemical study. J Cutan Pathol 28:453-459, 2001.
27. Shamsuddin AK, Nedwich A, Toker C: Lymphomatoid papulosis. Ultrastructural study with demonstration of intranuclear and intracytoplasmic viruslike particles. Dermatologica 161:238-242, 1980.
28. Kempf W, Kadin ME, Dvorak AM, et al: Endogenous retroviral elements, but not exogenous retroviruses, are detected in CD30-positive lymphoproliferative disorders of the skin. Carcinogenesis 24:301-306,
29. Ravat FE, Spittle MF, Russell-Jones R: Primary cutaneous T-cell lymphoma occurring after organ transplantation. J Am Acad Dermatol 54:668-675, 2006.
30. Wilkins K, Turner R, Dolev JC, et al: Cutaneous malignancy and human immunodeficiency virus disease. J Am Acad Dermatol 54:189-210 (incl quiz), 2006.
31. Dreno B, Milpied-Homsi B, Moreau P, et al: Cutaneous anaplastic T-cell lymphoma in a patient with human immunodeficiency virus infection: detection of Epstein-Barr virus DNA. Br J Dermatol 129:77-81, 1993.
32. Lucioni M, Ippoliti G, Campana C, et al: EBV positive primary cutaneous CD30+ large T-cell lymphoma in a heart transplanted patient: Case report. Am J Transplant 4:1915-1920, 2004.
33. Salama S: Primary "cutaneous" T-cell anaplastic large cell lymphoma, CD30+, neutrophil-rich variant with subcutaneous panniculitic lesions, in a post-renal transplant patient: Report of unusual case and literature review. Am J Dermatopathol 27:217-223, 2005.
34. Kleinhans M, Tun-Kyi A, Gilliet M, et al: Functional expression of the eotaxin receptor CCR3 in CD30+ cutaneous T-cell lymphoma. Blood 101:1487-1493,
35. Yamaguchi T, Ohshima K, Karube K, et al: Expression of chemokines and chemokine receptors in cutaneous CD30+ lymphoproliferative disorders. Br J Dermatol 154:904-909, 2006.
36. Yamamoto J, Adachi Y, Onoue Y, et al: Differential expression of the chemokine receptors by the Th1- and Th2-type effector populations within circulating CD4+ T cells. J Leukoc Biol 68:568-574, 2000.
37. Greisser J, Doebbeling U, Roos M, et al: Apoptosis in CD30-positive lymphoproliferative disorders of the skin. Exp Dermatol 14:380-385, 2005.
38. Wahl AF, Klussman K, Thompson JD, et al: The anti-CD30 monoclonal antibody SGN-30 promotes growth arrest and DNA fragmentation in vitro and affects antitumor activity in models of Hodgkin's disease. Cancer Res 62:3736-3742, 2002.
39. Mori M, Manuelli C, Pimpinelli N, et al: CD30-CD30 ligand interaction in primary cutaneous CD30(+) T-cell lymphomas: A clue to the pathophysiology of clinical regression. Blood 94:3077-3083, 1999.
40. Paulli M, Berti E, Boveri E, et al: Cutaneous CD30+ lymphoproliferative disorders: expression of bcl-2 and proteins of the tumor necrosis factor receptor superfamily. Hum Pathol 29:1223-1230, 1998.
41. Assaf C, Hummel M, Dippel E, et al: Common clonal T-cell origin in a patient with T-prolymphocytic leukaemia and associated cutaneous T-cell lymphomas. Br J Haematol 120:488-491, 2003.
42. Kadin ME: Pathobiology of CD30+ cutaneous T-cell lymphomas. J Cutan Pathol 33(suppl 1):10-17, 2006.
43. Whittaker S, Smith N, Jones RR, et al: Analysis of beta, gamma, and delta T-cell receptor genes in lymphomatoid papulosis: Cellular basis of two distinct histologic subsets. J Invest Dermatol 96:786-791, 1991.
44. Wood GS, Crooks CF, Uluer AZ: Lymphomatoid papulosis and associated cutaneous lymphoproliferative disorders exhibit a common clonal origin. J Invest Dermatol 105:51-55, 1995.
45. Dereure O, Levi E, Vonderheid EC, et al: Improved sensitivity of T-cell clonality detection in mycosis fungoides by hand microdissection and heteroduplex analysis. Arch Dermatol 139:1571-1575, 2003.
46. Steinhoff M, Hummel M, Anagnostopoulos I, et al: Single-cell analysis of CD30+ cells in lymphomatoid papulosis demonstrates a common clonal T-cell origin. Blood 100:578-584, 2002.
47. Gellrich S, Wernicke M, Wilks A, et al: The cell infiltrate in lymphomatoid papulosis comprises a mixture of polyclonal large atypical cells (CD30-positive) and smaller monoclonal T cells (CD30-negative). J Invest Dermatol 122:859-861, 2004.
48. Greisser J, Palmedo G, Sander C, et al: Detection of clonal rearrangement of T-cell receptor genes in the diagnosis of primary cutaneous CD30 lymphoproliferative disorders. J Cutan Pathol 33:711-715, 2006.
49. Rubben A, Kempf W, Kadin ME, et al: Multilineage progression of genetically unstable tumor subclones in cutaneous T-cell lymphoma. Exp Dermatol 13:472-483,
50. Peters K, Knoll JH, Kadin ME: Cytogenetic findings in regressing skin lesions of lymphomatoid papulosis. Cancer Genet Cytogenet 80:13-16, 1995.
51. Ott G, Katzenberger T, Siebert R, et al: Chromosomal abnormalities in nodal and extranodal CD30+ anaplastic large cell lymphomas: Infrequent detection of the t(2;5) in extranodal lymphomas. Genes Chromosomes Cancer 22:114-121, 1998.
52. Mao X, Orchard G, Lillington DM, et al: Genetic alterations in primary cutaneous CD30+ anaplastic large cell lymphoma. Genes Chromosomes Cancer 37:176-185, 2003.
53. Prochazkova M, Chevret E, Beylot-Barry M, et al: Chromosomal imbalances: a hallmark of tumour relapse in primary cutaneous CD30+ T-cell lymphoma. J Pathol 201:421-429, 2003.
54. Schiemann WP, Pfeifer WM, Levi E, et al: A deletion in the gene for transforming growth factor beta type I receptor abolishes growth regulation by transforming growth factor beta in a cutaneous T-cell lymphoma. Blood 94:2854-2861, 1999.
55. Kadin ME, Levi E, Kempf W: Progression of lymphomatoid papulosis to systemic lymphoma is associated with escape from growth inhibition by transforming growth factor-beta and CD30 ligand. Ann N Y Acad Sci 941:59-68, 2001.
56. Knaus PI, Lindemann D, DeCoteau JF, et al: A dominant inhibitory mutant of the type II transforming growth factor beta receptor in the malignant progression of a cutaneous T-cell lymphoma. Mol Cell Biol 16:3480-3489, 1996.
57. Rassidakis GZ, Thomaides A, Atwell C, et al: JunB expression is a common feature of CD30+ lymphomas and lymphomatoid papulosis. Mod Pathol 18:1365-1370, 2005.
58. Grange F, Bagot M: [Prognosis of primary cutaneous lymphomas]. Ann Dermatol Venereol 129:30-40, 2002.
59. Liu HL, Hoppe RT, Kohler S, et al: CD30+ cutaneous lymphoproliferative disorders: The Stanford experience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol 49:1049-1058, 2003.
60. Cabanillas F, Armitage J, Pugh WC, et al: Lymphomatoid papulosis: A T-cell dyscrasia with a propensity to transform into malignant lymphoma. Ann Intern Med 122:210-217, 1995.
61. Natkunam Y, Warnke RA, Haghighi B, et al: Co-expression of CD56 and CD30 in lymphomas with primary presentation in the skin: clinicopathologic, immunohistochemical and molecular analyses of seven cases. J Cutan Pathol 27:392-399, 2000.
62. 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 34:470-481, 1996.
63. Hughes PS: Treatment of lymphomatoid papulosis with imiquimod 5% cream. J Am Acad Dermatol 54:546-547, 2006.
64. Esteve E, Bagot M, Joly P, et al: A prospective study of cutaneous intolerance to topical mechlorethamine therapy in patients with cutaneous T-cell lymphomas. French Study Group of Cutaneous Lymphomas. Arch Dermatol 135:1349-1353, 1999.
65. Zackheim HS, Epstein EH Jr, Crain WR: Topical carmustine therapy for lymphomatoid papulosis. Arch Dermatol 121:1410-1414, 1985.
66. Didona B, Benucci R, Amerio P, et al: Primary cutaneous CD30+ T-cell lymphoma responsive to topical imiquimod (Aldara). Br J Dermatol 150:1198-1201, 2004.
67. Shehan JM, Kalaaji AN, Markovic SN, et al: Management of multifocal primary cutaneous CD30 anaplastic large cell lymphoma. J Am Acad Dermatol 51:103-110, 2004.
68. Calzavara-Pinton P, Venturini M, Sala R: Medium-dose UVA1 therapy of lymphomatoid papulosis. J Am Acad Dermatol 52:530-532, 2005.
69. Yagi H, Tokura Y, Furukawa F, et al: Th2 cytokine mRNA expression in primary cutaneous CD30-positive lymphoproliferative disorders: successful treatment with recombinant interferon-gamma. J Invest Dermatol 107:827-832, 1996.
70. French LE, Shapiro M, Junkins-Hopkins JM, et al: Regression of multifocal, skin-restricted, CD30-positive large T-cell lymphoma with interferon alfa and bexarotene therapy. J Am Acad Dermatol 45:914-918, 2001.
71. Wu JJ, Guitart J, Tucker RM, et al: Secondary cutaneous anaplastic large cell lymphoma treated with liposomal doxorubicin (Doxil) leading to complete remission. Int J Dermatol 42:464-465, 2003.
72. Mir SS, Richter BW, Duckett CS: Differential effects of CD30 activation in anaplastic large cell lymphoma and Hodgkin disease cells. Blood 96:4307-4312, 2000.
73. Forero A, Bernstein S, Gopal A, et al: Initial phase II results of SGN-30 (anti-CD30 mAb) in patients with refractory or recurrent systemic anaplastic large cell lymphoma (ALCL) (abstract 6001). J Clin Oncol 23:585s, 2005.
74. Duvic M, Kim Y, Reddy S, et al: 2006. Phase II preliminary results of SGN-30 (anti-CD30 mAb) in patients with CD30+ lymphoproliferative disorders (abstract 2733). Blood 108:773a.