ABSTRACT: Cutaneous lymphomas comprise a spectrum of diseases characterized by infiltration of the skin by malignant lymphocytes. The clinical manifestations of cutaneous lymphomas vary, and they can mimic benign dermatoses, as well as nodal or visceral malignancies with cutaneous spread. Cutaneous lymphomas are divided into T-cell lymphomas and B-cell lymphomas. Cutaneous T-cell lymphomas include mycosis fungoides, Szary syndrome, lymphomatoid papulosis, CD30+ large cell lymphoma, and adult T-cell leukemia/lymphoma. The extent and severity of skin manifestations in cutaneous T-cell lymphomas are prognostic indicators of extracutaneous involvement. Primary cutaneous B-cell lymphomas comprise 10% to 25% of all primary cutaneous non-Hodgkin's lymphomas and are classified according to their cell of origin. Most cutaneous B-cell lymphomas have an indolent course and excellent prognosis when compared to their nodal counterparts. Many factors have been implicated in the etiology of cutaneous lymphomas, including chemical and drug exposures, as well as microbial agents, such as the Epstein-Barr virus (EBV), human T-lymphocyte virus-1 (HTLV-1), and Borrelia burgdorferi. Immunohistochemistry and lymphocyte-receptor gene rearrangement studies are useful in distinguishing malignant from benign conditions. [ONCOLOGY 12(10):1521-1530, 1998]
Primary cutaneous lymphomas encompass a wide spectrum of both T- and B-cell lymphomas. They are the second most common group of extranodal non-Hodgkin’s lymphomas after primary gastrointestinal lymphomas. Primary cutaneous lymphomas have characteristic clinical behavior and histologic features, and their prognosis differs from that of primary nodal lymphomas of the same histologic subtype. Each case of cutaneous lymphoma must be assessed to determine whether it is of primary cutaneous origin or secondary to nodal and/or systemic disease.
Both cutaneous T-cell and B-cell lymphomas are further subdivided into different clinical entities. Within the spectrum of cutaneous T-cell lymphomas, mycosis fungoides is the most common subtype, comprising 50% of cases. Other less common clinical variants are the mycosis fungoides d’emblee variant, Woringer-Kolopp disease, Szary syndrome, alopecia mucinosa, poikiloderma vasculare atrophicans, lymphomatoid papulosis, CD30+ large cell lymphoma, and human T-lymphocyte virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma.
Cutaneous B-cell lymphomas are less common than cutaneous T-cell lymphomas and account for less than 20% of all primary cutaneous lymphomas. Unlike the cutaneous T-cell lymphomas, the different subtypes of cutaneous B-cell lymphoma may appear similar clinically, but they are distinguishable at the histopathologic and molecular level.
Cutaneous T-cell lymphoma is observed worldwide and affects both genders. Approximately 1,000 incident cases of cutaneous T-cell lymphoma occur annually in the United States. African-Americans experience the highest incidence rates, followed by Caucasians and Asian-Americans. Both incidence and mortality are higher in men than in women.[3,4]
Environmental Factors: Mycosis fungoides may be causally linked to chemical and nuclear exposures. A recent case-control study was conducted to determine whether exposure to chemicals in the workplace is related to an excess incidence of hematopoietic and lymphoid neoplasms. A positive association was found between exposure to chemicals and death due to non-Hodgkin’s lymphoma, multiple myeloma, and lymphoid leukemia at < 65 years of age.
On the other hand, Whittemore et al found no consistent relationship between occupational or chemical exposure and risk for mycosis fungoides. Another study conducted in Scotland showed no increased risk of childhood leukemia and non-Hodgkin’s lymphoma in cohorts of patients living near a nuclear site, but this study did not specifically mention cutaneous lymphoma.
Infectious Pathogens: Evidence implicating viral infections as possible etiologic or contributing factors has been sought since the isolation of HTLV-1, a type-C retrovirus, from the lymphocytes of a patient with cutaneous T-cell lymphoma. However, the restricted epidemiologic patterns (southwestern Japan, the West Indies, and southeastern United States) of HTLV-1 do not match the patterns of mycosis fungoides/Szary syndrome. In addition, serologic tests for HTLV-1 are negative in the majority of patients with mycosis fungoides/Szary syndrome.
The Epstein-Barr virus (EBV) genome has been found in B-cell lymphoma cells in persons with congenital or acquired immunodeficiency. Chronic infection with Borrelia burgdorferi has also been associated with low-grade B-cell lymphoma,[10,11] while some cases of gastric B-cell lymphoma have regressed after eradication of Helicobacter pylori.
Immunosuppression: Second malignancies occur with greater frequency in patients with cutaneous T-cell lymphoma, perhaps due to the immunosuppressive effect of the disease itself. On the other hand, immunosuppression may be a risk factor for cutaneous T-cell lymphoma. Human immunodefic-iency virus type 1 (HIV-1) infection is associated predominantly with aggres-sive B-cell lymphomas, but mycosis fungoides has now been reported among HIV-1-positive individuals.
Mycosis fungoides is a low-grade lymphoma of mature CD4+ cells. It is characterized by three phases of evolution: patch, plaque, and tumor. Patients may have lesions from the three different phases simultaneously.
Initially, mycosis fungoides consists of single or multiple, erythematous, scaly patches, occurring mainly over the trunk and extremities (Figure 1A). These patches are often associated with severe pruritus. The patch stage may last from months to years before progressing to the plaque stage.
Plaques are elevated, well-demarcated lesions that are oval or circular in shape. They may regress spontaneously or coalesce to form larger plaques.
In the tumor stage, the neoplastic cells enter a vertical growth phase, leading to the clinical appearance of an expanding nodule (Figure 1B).Tumors of mycosis fungoides have a predilection for the face and skin folds (eg, axillae, groin, and inframammary areas in women). Central necrosis with ulceration can occur, resulting in secondary bacterial infections.
Parapsoriasis en plaques is clinically and histologically indistinguishable from early patch-stage mycosis fungoides. Cutaneous manifestations of the former include red-brown, atrophic, scaly patches with a wrinkled cigarette paper-like surface (Figure 2). The size of these plaques varies from 1 to > 6 cm in diameter, and they typically occur on the trunk. Some authors regard parapsoriasis as a latent prelymphoma with the potential to transform into mycosis fungoides, whereas others believe it is simply an early form of mycosis fungoides.
The d’emblee variant of mycosis fungoides is a rare presentation in which tumors develop de novo without the long progression through patch and plaque stages. Affected patients tend to have an aggressive form of the disease and a poor prognosis.
Woringer-Kolopp disease, also known as pagetoid reticulosis, presents as a single, erythematous, scaly plaque, usually on the extremities. Extracutaneous spread has not been reported.
Szary syndrome, the leukemic variant of mycosis fungoides, constitutes approximately 5% of all newly reported cases of cutaneous T-cell lymphomas. It can arise de novo or as a progression from preexisting mycosis fungoides.
The malignant CD4+ cells circulate in the peripheral blood and populate the skin, creating diffuse erythroderma (Figure 3). Involvement of the face may lead to marked accentuation of facial folds, referred to as "leonine facies." There may be scaling and fissuring of the palms and soles, alopecia, ectro-pion, loss of nails, and ankle edema. The patient may complain of weight loss and malaise and may also experience fever and chills secondary to poor thermoregulation.
Examination of a peripheral blood smear shows hyperconvoluted lymphocytes with cerebriform nuclei, which, on immunophenotypic analysis, demonstrate a CD4+ CD7- phenotype. Investigators disagree as to how many circulating Szary cells are required to define the syndrome, but most agree that the consistent presence of more than 11% CD4+, CD7- lymphocytes, along with the appropriate clinical findings, can identify the disease. Occasionally, Szary cells are encountered in patients with benign dermatoses, such as psoriasis and atopic dermatitis, and even in healthy individuals.
1. Isaacson PG, Norton AJ: Cutaneous lymphoma, in Extranodal
Lymphomas, p 172. London, Churchill Livingstone, 1994.
2. Willemze R, Kerl H, Sterry W, et al: EORTC classification for the
primary cutaneous lymphomas: A proposal from the Cutaneous Lymphoma
Study Group of the European Organization for Research and Treatment
of Cancer. Blood 90:354-371, 1997.
3. Weinstock MA, Gardstein B: Twenty year trends in the reported
incidence of mycosis fungoides and its prognosis. J Invest Dermatol
4. Weinstock MA, Horm JW: Mycosis fungoides in the United States:
Increasing incidence and descriptive epidemiology. JAMA 260:42-46, 1988.
5. Massoudi BL, Talbott EO, Day RD, et al: A case-control study of
hematopoietic and lymphoid neoplasms: The role of work in the
chemical industry. Am J Ind Med 31:21-27, 1997.
6. Whittemore AS, Holly EA, Lee IM, et al: Mycosis fungoides in
relation to environmental exposures and immune response: A
case-control study. J Natl Cancer Inst 81:1560-1567, 1989.
7. Sharp L, Black RJ, Harkness EF, et al: Incidence of childhood
leukemia and non-Hodgkin’s lymphoma in the vicinity of nuclear
sites in Scotland. Occup Environ Med 53:823-831, 1996.
8. Poiesz BJ, Ruscetti FW, Gazdar AF, et al: Detection and isolation
of type C retrovirus particles from fresh and cultured lymphocytes of
a patient with cutaneous T cell lymphoma. Proc Natl Acad Sci USA
9. Levine AM: Acquired immunodeficiency syndrome-related lymphoma.
Blood 80:8-20, 1992.
10. Kutting B, Bonsmann G, Metze D, et al: Borrelia
burgdorferi-associated primary cutaneous B cell lymphoma: Complete
clearing of skin lesions after antibiotic pulse therapy or
intralesional injection of interferon alfa-2a. J Am Acad Dermatol
11. Garbe C, Stein H, Gollnick H, et al: Cutaneous B-cell lymphoma in
chronic Borrelia burgdorferi infection: Report of two cases and a
review of the literature. Hautarzt 39:717-726, 1988.
12. Bayerdorffer E, Neubauer A, Rudolph B, et al: Regression of
primary gastric lymphoma of mucosa-associated lymphoid tissue type
after cure of Helicobacter pylori infection. MALT Lymphoma Study
Group. Lancet 345:1591-1594, 1995.
13. Olsen EA, Delzell E, Jegasothy B: Second malignancies in
cutaneous T cell lymphoma. J Am Acad Dermatol 10:197-204, 1984.
14. Burns MK, Cooper KD: Cutaneous T-cell lymphoma associated with
HIV infection. J Am Acad Dermatol 29:394-399, 1993.
15. Kikuchi A, Naka W, Harada T, et al: Parapsoriasis en plaques: Its
potential for progression to malignant lymphoma. J Am Acad Dermatol
16. Carlotti A, Dallot A, Laroche L, et al: Cutaneous lymphomas of
the T cell type presenting primary tumors. Curr Probl Dermatol
17. Burns MK, Chan LS, Cooper KD: Woringer-Kolopp disease (localized
pagetoid reticulosis) or unilesional mycosis fungoides? An analysis
of eight cases with benign disease. Arch Dermatol 131:325-329, 1995.
18. Bogen SA, Pelley D, Charif M, et al: Immunophenotypic
identification of Sezary cells in peripheral blood. Am J Clin Pathol
19. Stolz W, Schmoeckel C, Burg G, et al: Circulating Sezary cells in
the diagnosis of Sezary syndrome (quantitative and morphometric
analyses). J Invest Dermatol 81:314-319, 1983.
20. Gibson LE, Muller SA, Leiferman KM, et al: Follicular mucinosis:
Clinical and histopathologic study. J Am Acad Dermatol 20:441-446, 1989.
21. Macaulay WL: Lymphomatoid papulosis: A continuing self-healing
eruption, clinically benign-histologically malignant. Arch Dermatol
22. McCarty MJ, Vukelja SJ, Sausville EA: Lymphomatoid papulosis
associated with Ki-1-positive anaplastic large cell lymphoma: A
report of two cases and a review of the literature. Cancer
23. 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.
24. Demierre MF, Goldberg LJ, Kadin ME, et al: Is it lymphoma or
lymphomatoid papulosis? J Am Acad Dermatol 36:765-772, 1997.
25. Willemze R, Beljaards RC: Spectrum of primary cutaneous CD30+
(Ki-1)-positive lymphoproliferative disorders. J Am Acad Dermatol
26. Kaudewitz P, Stein H, Dallenbach F, et al: Primary and secondary
cutaneous Ki-1+ (CD30+) anaplastic large cell lymphomas: Morphologic,
immunohistologic, and clinical characteristics. Am J Pathol
27. Cruickshank JK, Corbin DO, Bucher B, et al: HTLV-1 and
neurological disease. Baillieres Clin Neurol 1:61-81, 1992.
28. Hollsberg P, Hafler DA: Seminars in medicine of the Beth Israel
Hospital, Boston: Pathogenesis of diseases induced by human
lymphotropic virus type I infection. N Engl J Med 328:1173-1182, 1993.
29. Willemze R: New concepts in the classification of cutaneous
lymphomas. Arch Dermatol 131:1077-1080, 1995.
30. Vermeer MH, Geelen FA, van Haselen CW, et al: Primary cutaneous
large B-cell lymphoma of the legs: A distinct type of cutaneous
lymphoma with an intermediate prognosis: Dutch Cutaneous Lymphoma
Working Group. Arch Dermatol 132:1304-1308,1996.
31. Chang YT, Wong CK: Primary cutaneous plasmacytomas. Clin Exp
Dermatol 19:177-180, 1994.
32. LeBoit PE, McNutt NS, Reed JA, et al: Primary cutaneous
immunocytoma: A B-cell lymphoma that can easily be mistaken for
cutaneous lymphoid hyperplasia. Am J Surg Pathol 18:969-978, 1994.
33. Wick MR, Mills SE: Intravascular lymphomatosis: Clinicopathologic
features and differential diagnosis. Semin Diagn Pathol 8:91-101, 1991.
34. Carney DN, Bunn PA Jr: Manifestations of cutaneous T-cell
lymphoma. J Dermatol Surg Oncol 6:369-377, 1980.
35. Sausville EA, Worsham GF, Matthews MJ, et al: Histologic
assessment of lymph nodes in mycosis fungoides/Sezary syndrome
(cutaneous T-cell lymphoma): Clinical correlations and prognostic
import of a new classification system. Hum Pathol 16:1098-1109, 1985.
36. Lynch JW Jr, Linoilla I, Sausville EA, et al: Prognostic
implications of evaluation for lymph node involvement by T-cell
antigen receptor gene rearrangement in mycosis fungoides. Blood 79:3293-3299,
37. Stokar LM, Vonderheid EC, Abell E, et al: Clinical manifestations
of intrathoracic cutaneous T-cell lymphoma. Cancer 56:2694-2702, 1985.
38. O’Reilly GV, Clark TM, Crum CP: Skeletal involvement in
mycosis fungoides. Am J Roentgenol 129:741-743, 1977.
39. Griem ML, Moran EM, Ferguson DJ, et al: Staging procedures in
mycosis fungoides. Br J Cancer 31(suppl):362-367, 1975.
40. Paulli M, Bert 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, 1996.
41. Beljaards RC, Willemze R: The prognosis of patients with
lymphomatoid papulosis associated with malignant lymphomas. Br J
Dermatol 126:596-602, 1992.
42. Rhew DC, Gaultier CR, Daar ES, et al: Infections in patients with
chronic adult T-cell leukemia lymphoma: Case report and review. Clin
Infect Dis 21:1014-1018, 1995.
43. Burg G, Kaudewitz P: Where are we today in the diagnosis of
cutaneous lymphoma? Curr Probl Dermatol 19:90-104, 1990.
44. Santucci M, Pimpinelli N, Arganini L: Primary cutaneous B-cell
lymphoma: A unique type of low-grade lymphoma. Cancer 67:2311-2326, 1991.
45. Chu A, Berger CL, Kung P, et al: In situ identification of
Langerhans cells in the dermal infiltrate of cutaneous T cell
lymphoma. J Am Acad Dermatol 6:350-354, 1982.
46. Sanchez JL, Ackerman AB: The patch stage of mycosis fungoides:
Criteria for histologic diagnosis. Am J Dermatopathol 1:5-26, 1979.
47. Smoller BR, Glusac EJ: Histologic mimics of cutaneous lymphoma.
Pathol Annu 30:123-141, 1995.
48. Burg G, Kaudewitz P, Klepzig K: Cutaneous B-cell lymphoma.
Dermatol Clin 3:689-704.
49. Ackerman AB, Breza TS, Capland L: Spongiotic stimulants of
mycosis fungoides. Arch Dermatol 109:218-220, 1974.
50. Wallace ML, Smoller BR. Immunohistochemistry in diagnostic
dermatopathology. J Am Acad Dermatol 34:163-183, 1996.
51. Zelickson BD, Peters MS, Muller SA, et al: T-cell receptor gene
rearrangement analysis: cutaneous T cell lymphoma, peripheral T-cell
lymphoma, and premalignant and benign cutaneous lymphoproliferative
disorders. J Am Acad Dermatol 25:787-796, 1991.
52. D’Incan M, Souteyrand P, Bignon YJ, et al: Hydantoin-induced
cutaneous pseudolymphoma with clinical, pathologic, and immunologic
aspects of Sezary syndrome. Arch Dermatol 128:1371-1374,1992.
53. Callot V, Roujeau JC, Bagot M, et al: Drug-induced pseudolymphoma
and hypersensitivity syndrome: Two different clinical entities. Arch
Dermatol 132:1315-1321, 1996.
54. Crowson AN, Magro CM: Cutaneous pseudolymphoma: A review. J Clin
Dermatol 3:43-55, 1995.
55. Bunn PA Jr, Lamberg SI: Report of the Committee on Staging and
Classification of Cutaneous T-cell Lymphoma. Cancer Treat Rep
56. Kim YH, Jensen RA, Watanabe GL: Clinical stage IA (limited patch
and plaque) mycosis fungoides: A long term outcome analysis. Arch
Dermatol 132:1309-1313, 1996.
57. Kim YH, Bishop K, Varghese A: Prognostic factors in erythrodermic
mycosis fungoides and the Sezary syndrome. Arch Dermatol
58. Posner LE, Fossiek BE Jr, Eddy JL, et al: Septicemic
complications of the cutaneous T cell lymphomas. Am J Med 71:210-216, 1981.
59. Shimoyama M: Diagnostic criteria and classification of clinical
subtypes of adult T-cell leukemia lymphoma. Br J Haematol 79:428-437, 1991.
60. Tashiro T, Yamasaki T, Nagai H, et al: Immunological studies on
opportunistic infections and the development of adult T-cell
leukemia. Intern Med 31:1132-1136, 1992.
61. Pimpinelli N, Santucci M, Mori M, et al: Primary cutaneous B-cell
lymphoma: A clinically homogeneous entity? J Am Acad Dermatol
62. Kerl H, Cerroni L: The morphologic spectrum of cutaneous B-cell
lymphomas. Arch Dermatol 132:1376-1377, 1996.