AmericanJournal ofPatbology, Vol. 136, No. 4, April 1990 Copyright © American Association ofPathologists

Immunohistochemical Distinction of Lymphomatoid Papulosis and Pityriasis Lichenoides et Varioliformis Acuta Francis J. Varga,* Eric C. Vonderheid,t Suzanne M. Olbricht,t and Marshall E. Kadin* From the Departments ofPathology and Dermatology,* Harvard Medical School and Beth Israel Hospital, Boston, Massachusetts; and the Department ofDermatology,J Temple University Health Sciences Center, Philadelphia, Pennsylvania

Lymphomatoid papulosis (LyP) and pityriasis lichenoides et varioliformis acuta (PLEVA) are benign self-healing cutaneous eruptions that may be clinically and histologically similar. However LyP has a 5% to 20% risk ofassociated lymphoid malignancy, whereas PLEVA does not. To determine whether the immunophenotype of lymphoid cells is useful in the distinction of these two disorders, the pattern of expression of lymphoid cell lineage and activation antigens in nine cases of LyP and seven cases of PLEVA were compared. In all cases of LyP most larger cells expressed the activation antigen Ki- I (CD30) and lacked expression of the T-cell antigen CD7 and at least one other T-cell antigen (CD2, CD3, CD5). In contrast, CD30-antigen expression was rare or absent in PLEVA, CD3- and CD 7-antigen expression wasfound in all cases, and diminished expression of T-cell antigens (CD2 and CD5) was seen in only one case. Diffuse expression ofHLA-DR antigen by epidermal keratinocytes was found in a greater proportion of PLEVA cases (6 of 7) than LyP cases (3 of 6). In addition, CD8+ cells predominated at the dermal/epidermaljunction in 3 of 6 cases ofPLEVA but in only I of 7 cases ofLyP. We conclude that LyP and PLEVA can be distinguished immunohistochemically in most, ifnot all, cases. Furthermore these results suggest that LyP and PLEVA are separate disorders, thus accounting for their variable prognoses. (Am J Pathol 1990,

ously regressing cutaneous lesions. These are usually symmetrically distributed and most commonly involve the trunk and extremities. Papules are the most common lesions; they typically last 3 to 6 weeks. More persistent nodular lesions or associated patches or plaques are seen exclusively in LyP. Patients with LyP also tend to be older and have a longer duration of active disease.1 Histopathologic features reported to be of particular value in differentiating these disorders1 are summarized in Table 1. Although these differences usually allow the distinction of LyP from PLEVA, overlapping features make such distinction difficult in some cases. Therefore controversy continues as to whether LyP and PLEVA represent distinct clinicopathologic entities or variable manifestations of a common disorder.2'3 Clinically it is important to distinguish LyP and PLEVA because LyP but not PLEVA is reported to be associated with malignant lymphoma in 5% to 20% of cases at large referral centers.4-9 Although the incidence of malignant lymphoma occurring in patients with LyP outside these centers is uncertain, the potential for malignant evolution of LyP remains clinically relevant. Recent immunologic studies have not directly compared the immunophenotype of LyP and PLEVA with the aim of distinguishing these two disorders.1017 In addition, previous studies of LyP included few cases of LyP type B, which resembles mycosis fungoides and is easily confused histologically with PLEVA.18 In this study we report distinct immunohistochemical patterns that help to distinguish between LyP and PLEVA. The most useful features are the pattern of expression of the activation antigen CD30 (Ki-1) and T-cell differentiation antigens, particularly CD7. Immunohistochemical studies may therefore help in the distinction of LyP and PLEVA. In addition immunophenotypic evaluation may help to distinguish LyP, type B lesions from chronic or patch phase CTCL (cutaneous T-cell lymphoma), in which

136:979-987)

Pityriasis lichenoides et varioliformis acuta (PLEVA) and lymphomatoid papulosis (LyP) are lymphoproliferative disorders characterized by recurrent crops of spontane-

Supported by grant 254B from the American Cancer Society to Marshall E. Kadin. Accepted for publication December 8, 1989. Address reprint requests to Marshall E. Kadin, M.D. The Department of Pathology and Laboratory Medicine, 330 Brookline Ave, Boston, MA 02215.

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Table 1. Morphologic Criteria Used in this Study Epidermal changes Basal vacuolization, dyskeratosis, PLEVA para- or hyperkeratosis LyP, type A

Ulceration, pseudoepitheliomatous hyperplasia

LyP, type B

Minimal changes

Cellular composition of infiltrate Small lymphocytes with minimal atypia Large atypical cells resembling Reed-Sternberg cells, small lymphocytes, eosinophils, neutrophils, occasional CMCs CMCs predominate, small lymphocytes, occasional neutrophils

Pattern of infiltrate Perivascular and at dermal/epidermal

junction Perivascular, wedge shaped Perivascular, epidermotropic

CMCs, cerebrform mononuclear cells. occ., occasional.

the lymphocytic infiltrate usually lacks or contains only few

CD30+ cells.","

Materials and Methods Sixteen patients with spontaneously regressing skin eruptions referred to the Beth Israel Hospital of Boston or the Skin and Cancer Hospital of Philadelphia were evaluated. Each patient had one to four punch or elliptical biopsies of skin studied by histology and immunopathology. Cases were classified histologically as LyP type A, LyP type B, or PLEVA according to the histologic features described by Willemze and others (Table 1, Figures 1 and 2).18 Because it is often difficult to separate LyP type A from type B, and LyP from PLEVA, for the purposes of this paper such ambiguous cases were excluded. From this evaluation, 6 cases were classified as LyP, type A, 3 as LyP, type B, and 7 as PLEVA. Skin biopsy specimens from all but two patients (patients 3 and 15) were fixed in periodate-lysine-paraformaldehyde (PLP) fixative and immunohistochemical analysis was performed as previously described.10 In one case (patient 3) immunohistochemical studies were performed

on unfixed frozen tissue and in another (patient 15) on formalin-fixed paraffin-embedded tissue. The antibodies used in this study and their sources and specificities are given in Table 2. The evaluation of antigen expression differed between histologic groups because of differences in cellular composition and the pattern of the infiltrate. In LyP types A and B, distinct populations of larger and smaller cells could be recognized, allowing for their separate evaluation. The infiltrate in cases of LyP type A was evaluated only within the dermis because a significant infiltrate at the dermal epidermal junction (DEJ) was not present. In LyP type B and PLEVA, however, there was a significant infiltrate at the DEJ, allowing for the separate immunohistochemical evaluation of the infiltrate within the dermis and at the DEJ. A semiquantitative assessment of antigen expression was used, as in previous evaluations of CTCL in our laboratory.'9 Only the relative expression of T-helper/inducer (CD4+) and T-cytotoxic/suppressor (CD8+) subset antigens was noted (Results). Epidermal expression of HLA-DR was also evaluated. Expression was considered diffuse when virtually all epidermal keratinocytes showed strong surface positivity, patchy when there was variable or geographic epidermal gv e Figure 1. Histology of LyP. The dermal in3' B_>. filtrate > is composed of small lymphocytes, neutrophils, and large atypical cells frequently resembling Reed-Stemnberg cells (inset). The epidermis is thinned and infil-

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Immunopathology of LyP and PLEVA

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Table 4. Pattern ofExpression ofActivation Antigens CD30 (Ki-1)

CD25 (Tac)

HLA expression

by epidermal

Cell size/patient LYP, TYPE A

Large

Small

Large

Small

keratinocytes§

1 2 3 4 5 6 LYP, TYPE B 7 8 9

+++ +++ +++ +++ +++ +++

+ +

+++ +++

++ +

-

+ _

-

+++ +++ +++

Negative nd Diffuse nd

+

Negative

-

+++-

++/±t

-/±t

Cell size PLEVA 10

+++/-t +++ +++

++ +

CD30 (Ki-1) All cellst

13

Diffuse Negative Diffuse

nd

+/++t

Diffuse

+/++t +

+

+ +

Patchy Diffuse Diffuse Diffuse Diffuse Diffuse

+ + +

-/+t

CD25 (Tac) All cellst

±/+t

11 12 14 15* 16

+++ +++

nd

* Paraffin sections studied with monoclonal antibodies Ber-H2 (Ki-1) and LN3 (la). +++, >50% positive; ++, 20% to 50% positive; +, occasional to 20% positive; ±, occasional; -, negative; nd, not done. t Where significantly different, cells within the dermis and at the dermal epidermal junction are graded separately (dermis/DEJ). t Distinct populations of smaller and larger cells are not readily identifiable. § See Materials and Methods section.

Hodgkin's disease-associated activation antigen CD30 (Figure 3). In two of three cases of LyP type B, expression of CD30 antigen was also demonstrated by 20% to 50% of smaller cells. In contrast, CD30 expression was absent or limited to only rare cells in PLEVA. The large atypical cells of LyP also expressed the activation antigen CD25 in all but one case. In three cases of PLEVA, a greater proportion of cells at the DEJ than within the dermis expressed CD25. Such a gradient of CD25 expression was seen only in one case of LyP (type B, case 7). The majority of large cells in all cases of LyP except one (patient 7) expressed HLA-DR (data not shown), as did the majority of smaller cells in two of five cases evaluated. Most lymphoid cells in three of six cases of PLEVA also appeared to express HLA-DR. The large atypical cells in five of the nine cases of LyP expressed T-cell antigens (Table 5). In all LyP cases the large atypical cells failed to express the T-cell antigen CD7 and at least one additional T-cell antigen (CD2, CD3, or CD5). In five of nine cases of LyP, CD7 expression also appeared diminished on small lymphocytes. In contrast, in only one case (patient 12) of PLEVA was there diminished expression of T-cell antigens (CD2 and CD5), and in no case of PLEVA in which the test was performed was there lack of expression of CD7. The large atypical cells in LyP expressed a T helper/ inducer (CD4+) phenotype in five cases, and neither a T helper/inducer nor cytotoxic/suppressor phenotype in four cases (Table 6). In all cases of LyP and PLEVA ex-

cept one (case 3) the number of CD4+ small lymphocytes within the dermis was greater than (11 cases) or equal to (3 cases) the number of CD8+ cells. In three of six cases of PLEVA and one of three cases of LyP type B, CD8+ cells predominated (Figure 4). In six of seven cases of PLEVA nearly all epidermal keratinocytes expressed HLA-DR (diffuse positivity) (Figure 5). In the remaining case, HLA-DR expression was patchy. In LyP, diffuse positivity of keratinocytes was seen in three of six cases studied.

Discussion The results of this study show distinct immunohistochemical differences between active lesions of LyP and PLEVA. The most consistent difference is the uniform expression of the Hodgkin's disease-associated activation antigen CD30 and the more frequent expression of CD25 by the large atypical cells in lymphomatoid papulosis but not the infiltrating cells in PLEVA. Another distinguishing feature is the diminished expression of CD7 and at least one other T-cell antigen in LyP compared with PLEVA, where absence of T-cell antigen expression (CD2 and CD5) was found in only one of seven cases. Increased numbers of cytotoxic/suppressor (CD8+) and CD25+ T cells at the DEJ were more commonly seen in PLEVA than in LyP. These differences suggest that lymphoid cells in lesions

984 Varga et al AJPApril 1990, Vol. 136, No. 4 Table 5. Pattern of T-antigen Expression

Cell size Patient LYP Type A 1 2 3 4 5

6 LYP Type B 7

Large

Small

Large

Small

Large

-

+++ +++

-

++ +++

+

-

nd ++ +++

+ +++ wk nd +++ nd wk

8 9 PLEVA

10 11 12 13

wk nd

+

-

+++ +++ +++

+++

+++

+++

nd wk

-

+++

CD7

CD5

CD3

CD2

Antigen/

Small

nd +++ + +++ +++

-+++

-+++ + + +++++

-

+++ ++

+++

+++++

++

Small

Large

-

+

-+++ ++ -

all cells* +++ +++

+ +++ +++ nd

14 15 16

+++

+++

+++

+ +++

+++

+++

nd

nd

nd

+++, >50% positive; ++, 20% to 50% positive; +, occasional to 20% positive; ±, occasional; -, negative; nd, not done; na, not applicable; wk, weak. Distinct populations of smaller and larger cells are not readily identifiable.

*

of LyP and PLEVA have distinct immunophenotypic features. This distinction is conveniently associated with observed clinical differences between these two disorders, the most important of which is the well-documented association of LyP3-9 but not PLEVA with malignant lymphoma. These distinct immunohistochemical features may have practical diagnostic value. Although reported clinical and histologic differences allow the distinction of LyP and PLEVA in most instances (Table 1),1 differentiation of early or resolving lesions18 is more difficult. The pattern of the cellular infiltrate in both is similar, the cellular atypia characteristic of LyP, type B may be difficult to discern in improperly fixed tissue, and the epidermal changes required for a diagnosis of PLEVA may be slight. Molecular genetic studies may not be helpful because recent reports have demonstrated clonal rearrangements of the T-cell receptor beta chain genes in both LyP and PLEVA.20-22

The similar immunophenotypic features of LyP types A and B support the hypothesis that both lesions represent variable manifestations of a common disorder based on previous observations of overlapping clinical and histo-

B.: Figure 3. Expression of CD30 (Ki-1) in mature lesion lymphomatoid papulosis. Most dermal infiltrating cells strongly express CD30 (Ki-1). The overlying epidermis is ulcerated and covered with crust (case 2 immunoperoxidase, X240).

_>

_. , *,

>.

>

Figure 4. Functional T-cell subset antigen expression in PLEVA. A: Most cells at the dermal epidermal junction express CD8. B: Frequent perivascular cells express CD4, but CD4+ cells are rare at the dermal/epidermaljunction (case 10, ABC, X240).

Immunopathology of LyP and PLEVA

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AJPApril 1990, Vol. 136, No. 4

Table 6. Pattern ofExpression of T-Helper (CD4+) and Suppressor (CD8+) Antigens

Dermal/epidermal junction

Dermis

Location Cell size

Large

Large

Small

Small

Patient

Predominant population LYP Type A 1 2 3 4 5 6 LYP Type B 7 8 9 PLEVA 10 11 12 13 14 15 16

CD4 CD4 Both absent CD4 CD4 Both absent

CD4 CD4 CD8 CD4 CD4 CD4

na* na na na na

na na na na na

na

na

Both absent Both absent CD4

Equal CD4 CD4

Both absent Both absent

CD4

CD8 CD4 CD4

nat

CD4 Equal CD4 Equal CD4 na CD4

na na na na na na na

CD8 CD8 CD4 CD8 CD4 nd CD4

na na na na na

na

na, not applicable; nd, not done. * Only infrequent cells at dermal/epiderrnal junction. t Distinct populations of smaller and larger cells are not readily identifiable.

logic features."6 The demonstration of immunophenotypic differences between LyP, type B, and PLEVA is of particular diagnostic utility because these two disorders may be difficult to distinguish histologically. These results suggest that immunophenotypic analysis may help to distinguish type B LyP from early cutaneous T-cell lymphoma (CTCL), which is also characterized by an epidermotropic infiltrate of hyperchromatic cerebriform cells. Although morphologic criteria have been defined to separate LyP type B from CTCL,16 some cases remain difficult to distinguish. The infiltrate in patch and plaque stage CTCL has been found to contain only few CD30+ cells,10'12 whereas this study demonstrates many CD30+ cells in type B LyP. The expression of the Hodgkin's disease-associated activation antigen CD30 by the atypical cells in most or all cases of LyP is consistent with most previous studies, 10'1317 as is the absent or minimal expression of CD30 antigen in PLEVA.16 The study of Wood et al,16 however, found no significant differences in CD30 antigen expression or other phenotypic differences between LyP and PLEVA. This appears to be due, in part, to a low prevalence of CD30 positivity in their cases designated as LyP. We suggest that this could be due to technical factors such as the use of frozen tissue rather than PLP-fixed tissue10 used in this study, or to the criteria used for patient selection. Furthermore, it may be difficult to detect CD30+ cells in early or resolving lesions of LyP. Our results are consistent with recent studies of the distribution

of CD30 antigen expression in a broad range of benign and malignant cutaneous lymphoid lesions, as determined by Ralfkiaer et al12 and van der Putte et al.17 The infiltrates in both LyP and PLEVA were found to express other activation antigens such as CD25 and HLADR. In PLEVA, however, preferential expression of CD25 was found only at the DEJ. This was associated with the usual strong and diffuse expression of HLA-DR by the overlying epidermal keratinocytes. By comparison, a gradient of CD25 expression was not seen in LyP and epidermal expression of HLA-DR was inconsistent. Similar to CD25+, CD8+ cells were concentrated at the DEJ in three of six cases of PLEVA. Our result is similar to previous studies of PLEVA1416 and suggests that activated CD8+, CD25+ cells of PLEVA liberate cytokines responsible for epidermal damage. The predominance of CD4+ cells at the DEJ in three cases of PLEVA in this study has not been previously reported to our knowledge, although a predominance of CD4+ cells has been observed in cases of pityriasis lichenoides chronica16 or in early or resolving lesions of PLEVA.14 These results suggest that cytotoxic damage and diffuse expression of HLA-DR may be mediated by either CD4+ or CD8+ T cells. A subset of CD4+ T cells (in-

4

.

-

q'. *

Figure 5. Differential expression ofHLA-DR by epidermal keratinocytes in PLEVA and lymphomatoidpapulosis. A: Epidermal keratinocytes strongly express Ia in almost all cases of PLEVA, as seen in this case (case 12). B: Expression ofIa by epidermal keratinocytes is much more variable in LyP, and is completely absent in this case (case 4). Epidermal Langerhan's cells and the dermal infiltrate, however, are strongly Ia positive (immunoperoxidase, X240).

986 Varga et al AJPApril 1990, Vol. 136, No. 4

flammatory T cells) has been shown to release cytotoxic factors similar to those of CD8+ cytotoxic/suppressor T cells.23 These include gamma interferon, which has been reported to induce HLA-DR expression by cultured epidermal keratinocytes in vitro.24 Further analysis of PLEVA with antibodies capable of distinguishing the different CD4+ subsets would therefore be of interest. Aberrant expression of lymphoid antigens appears to further distinguish LyP from PLEVA. The atypical cells in LyP uniformly lack expression of CD7 and variably lack expression of other T-cell antigens (CD2, CD3, and CD5), which is consistent with previous reports.10-14 In this study expression of CD7 by smaller cells also appeared diminished in some cases of LyP. These findings contrast with PLEVA in which the lymphoid infiltrates uniformly expressed CD7 and lacked expression of T-cell antigens (CD2, CD5) in only one case. Lack of expression of CD5 as well as CD2 and CD4 recently has been reported in PLEVA.25 Diminished expression of CD7 is commonly seen in malignant lymphomas that are associated with LyP, including Hodgkin's disease,26 mycosis fungoides,"8 and CD30+ large-cell lymphomas.27 Although not limited to malignant cutaneous disorders,28'9 diminished expression of CD7 has been found to be significantly greater in neoplastic infiltrates, such as CTCL, as compared with benign cutaneous lymphoproliferative disorders.3 This study illustrates distinct immunophenotypic differences between LyP and PLEVA and suggests that they may be separate disorders. These findings are novel because other authors have suggested that these two disorders are closely related or even indistinguishable based on certain common clinical, histologic, and immunophenotypic features, including the recent finding of clonal T-cell antigen receptor gene rearrangements in both LyP and PLEVA.Y22 In contrast to this view, we conclude that analysis of the pattern of antigen expression in LyP and PLEVA can separate these two disorders and thereby separate groups of patients at greater or lesser risk to develop malignant lymphoma.

References 1. Willemze R. Scheffer E: Clinical and histological differentiation between lymphomatoid papulosis and pityriasis lichenoides. J Am Acad Dermatol 1985,13:418-428 2. Black MM: Lymphomatoid papulosis and pityriasis lichenoides. Are they related? Br J Dermatol 1982, 106:717-721 3. Weinman VF, Ackerman AB: Lymphomatoid papulosis: A critical review and new findings. Am J Dermatopathol 1981,

3:129-163 4. Sanchez NP, Pittelkow MR, Muller SA, Banks PM, Winkelmann RK: The clinicopathological spectrum of lymphomatoid papulosis: Study of 31 cases. J Am Acad Dermatol

1983,8:81-94

5. Sina B, Bumett JW: Lymphomatoid papulosis: Case reports and review of the literature. Arch Dermatol 1983,119:189-197 6. Fine RM, Meltzer HD, Rudner EJ: Lymphomatoid papulosis eventuating in mycosis fungoides. South Med J 1981, 67: 1492-1497 7. Madison JF, O'Keefe TE, Meier FA, Clendenning WE: Lymphomatoid papulosis terminating as cutaneous T cell lymphoma (mycosis fungoides). J Am Acad Dermatol 1983, 9: 743-747 8. Tucker WFG, Leonard JN, Smith N, Coulter C, Woods B, Clayton RJ: Lymphomatoid papulosis progressing to immunoblastic lymphoma. Clin Exp Dermatol 1984,9:109-115 9. Chen KT, Flam MS: Hodgkin's disease complicating lymphomatoid papulosis. Am J Dermatopath 1985, 7:555-561 10. Kadin M, Nasu K, Sako D, Said J, Vonderheid E: Lymphomatoid papulosis: A cutaneous proliferation of activated helper T cells expressing Hodgkin's disease associated antigens. Am J Pathol 1985,119:315-325 11. Kaudewitz P, Stein H, Burg G, Mason DY, Braun-Falco 0: Atypical cells in lymphomatoid papulosis express the Hodgkin's cell associated antigen Ki-1. J Invest Dermatol 1986, 86:350-354 12. Ralfkiaer E, Bosq J, Gatter KC, Schwarting R, Gerdes J, Stein H, Mason DY: Expression of a Hodgkin's and Reed Stemberg cell associated antigen (Ki-1) in cutaneous lymphoid infiltrates. Arch Dermatol Res 1987,279:285-292 13. Wood GS, Strickler JG, Deneau DG, Egbert B, Warnke RA: Lymphomatoid papulosis expresses immunophenotypes associated with T cell lymphoma but not inflammation. J Am Acad Dermatol 1986,15:444-458 14. Muhlbauer JE, Bhan AK, Harnst TJ, Moscicki RA, Rand R, Caughman W, Loss B, Mihm MC: Immunopathology of pityriasis lichenoides acuta. J Am Acad Dermatol 1984,10:783-795 15. Giannetti A, Girolomoni G, Pincelli C, Benassi L: Immunopathologic studies on pityriasis lichenoides. Arch Dermatol Res 1988, 280(Suppl):S61-65 16. Wood GS, Strickler JG, Abel EA, Deneau DG, Warnke RA: Immunohistology of pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica: Evidence for their interrelationship with lymphomatoid papulosis. J Am Acad Dermatol 1987,16:559-570 17. van der Putte SC, Toonstra J, van Wichen DF, van Unnik JA, van Vloten WA: The expression of the Hodgkin's disease associated antigen Ki-1 in cutaneous infiltrates. ACTA Derm Venereol (Stockh) 1988, 68:202-208 18. Willemze R, Meyer CJ, van Vloten WH, Scheffer E: The clinical and histological spectrum of lymphomatoid papulosis. Br J Dermatol 1982,107:131-144 19. Nasu K, Said J, Vonderheid EC, Olerud J, Sako D, Kadin ME: Immunopathology of cutaneous T cell lymphomas. Am J Pathol 1985,119:436-447 20. Weiss LM, Wood GS, Ellisen LW, Reynolds TC, Sklar J: Clonal T cell populations in pityriasis lichenoides et varioliformis acuta. Am J Pathol 1987,126:417-421 21. Weiss LM, Wood GS, Warnke RA, Sklar J: Clonal T cell populations in lymphomatoid papulosis. Evidence of a lymphoproliferative origin for a clinically benign disorder. N EngI J Med 1986, 315:475-479

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22. Kadin ME, Vonderheid EC, Sako D, Clayton LK, Olbricht S: Clonal composition of T cells in lymphomatoid papulosis. Am J Pathol 1987,126:13-17 23. Janeway CA, Carding S, Jones B, Murray J, Portoles P, Rasmussen R, Rojo J, Saizawa K, West J, Bottomly K: CD4+ T cells: Specificity and function. Immunol Rev 1988, 101:39-80 24. Basham TY, Nickoloff BJ, Menigan TC, Morhenn VB: Recombinant gamma interferon induces HLA-DR expression on cultured human keratinocytes. J Invest Dermatol 1984, 83:88-90 25. Toonstra J, van der Putte SC, van Wichen DF, van Eijk C, van Vloten WA: Loss of T cell markers in pityriasis lichenoides. Abstracts from the International Symposium of Cutaneous Lymphomas, Copenhagen, October 28-30,1988. p. 17 26. Kadin ME, Muramoto L, Said J: Expression of T cell antigens on Reed Sternberg cells in a subset of patients with nodular sclerosing and mixed cellularity Hodgkin's disease. Am J Pathol 1988, 130:345-353

27. Kadin ME, Sako D, Berliner N, Franklin W, Woda B, Borowitz M, Ireland K, Schweid A, Herzog P, Lange B, Dorfman R: Childhood Ki-1 lymphoma presenting with skin lesions and peripheral adenopathy. Blood 1986, 68:10421049 28. Haynes BF, Metzgar RS, Minna JD, Bunn PA: Phenotypic characterization of cutaneous T cell lymphoma. Use of monoclonal antibodies to compared with other malignant Tcells. N Engl J Med 1981, 304:1319-1323 29. Haynes BF, Hensley LL, Jegasothy BV: Phenotypic characterization of skin infiltrating T cells in cutaneous T cell lymphoma: Comparison with benign cutaneous T cell infiltrates. Blood 1982, 60:463-473 30. Wood GS, Abel EA, Hoppe RT, Warnke RA: Leu 8 and Leu 9 antigen phenotypes, immunological criteria for the distinction of mycosis fungoides from chronic inflammation. J Am Acad Dermatol 1986, 14:1006-1013