2Professor, Department of Dermatology, Boston University and Roger Williams Medical Center, Providence, RI, USA
3Associate Professor, Department of Dermatology, The Warren Alpert Medical School of Brown University, RI, USA
Methods: This observation prompted us to review our experience with cases initially diagnosed as LyP or “lymphomatoid” pityriasis lichenoides for CD30 expression by epidermotropic T cells.
Results: CD30 expression by more than 20% of the epidermotropic T cells was observed in a group of 10 cases characterized clinically by self-healing papulonodules (two cases also with infiltrated plaques) and pathologically by atypical lymphocytes with cerebriform nuclei within the epidermis and dermal infiltrate.
Conclusions: CD30 can be expressed by either CD4+ or CD8+ cells in cases of LyP with epidermotropic T cells (so-called mixed LyP type A/B), but three of our cases appear to be examples of lymphomatoid CD30+ PLEVA. In addition, three cases had serologic manifestations suggestive of a lupus erythematosus-like autoimmune disorder. We hypothesize that CD30+ lymphocytes with cerebriform nuclei in some cases result in accumulation of benign activated CD8+ and CD4+ T cells rather than neoplastic cells.
Keywords: LYP (lymphomatoid papulosis); CD30; PLEVA (pityriasis lichenoides et varioliformis acuta); Lupus Erythematosus
Kempf's paper prompted us to review our experience with patients initially diagnosed to have LyP or "lymphomatoid" pityriasis lichenoides for CD30 expression by epidermotropic T cells. We discovered that CD30 expression by more than 20% of the epidermotropic T cells identifies a heterogeneous group characterized clinically by self-healing papules and occasionally small nodules (two cases also with infiltrated plaques) and pathologically by atypical lymphocytes with convoluted or cerebriform nuclei (cerebriform lymphocytes) within the epidermis and dermal infiltrate. Three of our 10 patients may have CD30+ PLEVA although one patient (described below) also had specimens that were typical of LyP, an observation that supports the concept of a close pathogenic relationship exists between these conditions. [3, 5, 6] We also discovered a possible association of CD30+ cutaneous lymphoproliferative disorders with undeclared lupus erythematosus.
Patient 6 illustrates that skin specimens obtained at different times can vary between pityriasis lichenoides and LyP. Prior to referral, two specimens showed characteristic features of pityriasis lichenoides with absent or rare CD30+ dermal cells and two other specimens showed features typical for LyP-A with many CD30+ cells in the dermis (Figures 1 and 2).
The papule from patient 7, who had co-existing patch phase mycosis fungoides, had typical histopathologic features of LyPA/ B with 20% CD30+ cells within the epidermis, but without CD30+ cells in the dermal infiltrate despite the presence of
Patient 8, who had been diagnosed to have LyP-A (histopathology only), presented with self-healing papules with histologic features of LyP-C, specifically a wedge-shaped infiltrate containing numerous large atypical cells with prominent nucleoli including Reed-Sternberg-like cells, many eosinophils and mitotic figures, extravasated erythrocytes, and margination of neutrophils in blood vessels (Table 1, Figure 4). The immunophenotype of these atypical cells was CD8+CD4- CD30+ indicating the possibility of aggressive primary cutaneous epidermotropic CD8+ cytotoxic T-cell lymphoma, also known as Berti’s lymphoma. [10, 11] The infiltrate was not angiocentric nor was vasculitis present, features characteristic of LyP-E. [12] Epidermotropic T cells were CD8+ and approximately one-half expressed of CD30. Although the patient’s disease responded well to low doses of methotrexate, her disease would abruptly recur when methotrexate doses were reduced. (Figure 5). Seven and one half years after initial presentation, the patient developed a 3 cm tumor on her palm. The biopsy specimen contained a dense nodular dermal infiltrate of morphologically similar cells as the initial specimen with 80% of cells expressing CD30. A diagnosis
Case |
A/R/G |
Duration; Clinical Examination; |
Epidermal Changes |
Dermal Changes |
Lymphocytes |
Immunohistochemistry |
TCR-γ |
Final DX |
1
|
52WF |
4 mo; Regressed Paps plus 2.3 cm PQ; |
Ep (many) |
Li, PV, I, PA, M |
Medium-large HC CLs and LVC |
ED: 100% CD2+3+4+8-5-7-62L-CD30+; |
Pos (SSCP) |
LyP-C/ |
2 |
50WF |
5 mo; |
U, Ep (many) |
Li, PV, Neu (v), EE, M |
Medium-large HC CLs plus LVC/RSC in dermis |
ED: 100% CD2+3+4+5+7+8-62L+, 50% CD30+; |
ND |
LyP-A/B |
3 |
34BF |
5 yr; |
U/N, A, Ep (many) |
PV, I, SC, PDE, Eos, EE, Vas |
CLs plus LVC in dermis |
ED: CD4 >> CD8, |
Neg (SSCP) |
LyP-A/B |
4 |
12 WF |
1 yr; |
A, P, Ep (many) |
Li, PV, PA, EE |
Small CLs plus few medium sized CLs in dermis |
E: CD8 > CD4, scattered CD30+;* |
Neg (DGGE) |
LyP-A/B |
5 |
16 WF |
5 mo; |
A, P, U, Ep (many) |
Li, PV, PDE, EE, Eos, Vas, PA |
Medium, occasional large HC CLs also in dermis |
ED: CD8 > CD4, |
Neg (SSCP) |
LyP-A/B |
6 |
35WF |
15 mo; |
U, Ep (many) |
Li, PV, EE, Neu (v) |
Medium-large CLs |
ED: CD8 > CD4, |
Pos (DGGE) |
LyP-A/B |
7 |
36 WM |
7 yr; Ulcerated & crusted Paps + PTs ≤ 5 cm‡; |
A, U, Ep (B, many) |
Li, PV, MF, Neu (v), EE |
Medium-large HC CLs plus LVC in dermis |
E: CD8 >> CD4, 20% CD30+; |
ND |
LyP-A/B |
8
|
78WF |
12 yr; |
U, Ep (focal?) |
Li, PV, MF, Eos, EE, Neu (v) |
Small CLs, LVC/RSC |
ED: CD8 >> CD4, > 50% CD30+; |
ND |
LyP-C |
9 |
77WF |
2 yr; |
U, VA, Ep (many) |
PV, Neu (v), EE |
Medium-large HC CLs |
ED: Weak CD4 & CD8§, CD30+; |
ND |
LyP-B§ |
10 |
59 WF |
5 yr; |
A, VA, NK, EE, Ep (Many, basalar) |
Li, W, EE, Eos |
Medium-large HC CLs also dermis |
ED: CD4 = CD8, many CD30+*; |
Neg (DGGE) |
See discussion |
* Not indicated which T cell subset is expressing CD30
‡ Biopsy specimen of patch diagnostic for mycosis fungoides
# Subacute lupus erythematosus favored as diagnosis, but anti-SSA/Ro and anti-SSB/La antibodies negative.
§ Large cerebriform cells express CD2, CD3, CD5, CD7, CD62L, and CD30 but stain weakly for CD4 and CD8.
A papule from patient 9 had no CD30+ cells in the dermal infiltrate and was diagnosed as LyP-B. The large intraepithelial T cells in this case expressed an unusual CD3+CD4dimCD8dimCD30+ immunophenotype. In addition these cells expressed CD2, variable CD5, CD7, and CD62L. The CD4 CD8 double positive phenotype has been observed in a few cases of LyP-A or LyP-C including one case with the 6p25.3 translocation [9, 14-15] and mycosis fungoides. [15] It is also possible that CD4+CD8+ neoplastic T cells differentiated from double negative precursor cells under influence of thymic-like hormones produced in vivo by keratinocytes. [16] However, CD1 was not expressed, a finding that argues against differentiation from immature thymocytes. Alternatively, stimulation of CD4+ neoplastic T cells in the epidermis might have induced expression of CD8. [17]
Finally, similar to patient 1, patient 10 presented with scattered self-healing 3 to 15 mm papulonodules along with two infiltrated plaques on the face and antecubital fossa. (Figures 6 and 7). A biopsy obtained from a papule 3 months before referral showed some vacuolar interface alteration and extravasated erythrocytes, but also lymphocytes with enlarged hyperchromatic and somewhat pleomorphic nuclei in the dermal infiltrate. (Figure 8) These atypical cells were CD30-negative and the tentative diagnosis was lymphomatoid pityriasis lichenoides.
This patient also had a prior history of urticarial vasculitis and photosensitivity, suggesting that the facial plaques were a manifestation of subacute lupus erythematosus although this could not be confirmed by serologic studies. The specimen taken from a small plaque on the thigh showed a band-like dermal infiltrate, vacuolar interface alterations with apoptotic keratinocytes, but also many small-medium sized cerebriform lymphocytes in the epidermis and superficial dermis that supported a diagnosis of mycosis fungoides (Figures 9 and 10). The epidermotropic cells consisted of a mixture of CD4+ and CD8+ cells, many of which expressed CD30 and scattered CD30+
In addition to patient 10, two other patients in this series (cases 2 and 6) had manifestations suspicious for a concomitant connective tissue disorder. Specifically, patient 2 had fatigue, arthralgias, positive antinuclear antibody (1:1280 titer, homogeneous pattern), elevated sedimentation rate, biologic false positive RPR, and thrombocytopenia, but no antibodies against double-stranded DNA, cardiolipin, SSA/Ro, SSB/La, and extractable nuclear antigens. Patient 6 also had fatigue, arthralgias, positive antinuclear antibody (1:640 titer, nucleolar and fine speckled pattern) and single-stranded DNA antibody tests, but negative double-stranded DNA antibody and other autoimmune serologies including anti-SSA/Ro and SSB/La antibodies.
We conclude that CD30 may be rarely expressed not only by CD8+ cells in some cases of PLEVA as reported by Kempf, [3] but also by epidermotropic T cells in lesions with histopathologic features of LyP. Our observation that one of our patients had both types of lesions suggests the possibility of a related histogenesis between LyP and CD30+ PLEVA, We demonstrate the variability of CD30 positivity in this heterogeneous population of selfhealing papulonodules. Furthermore, some patients with CD30+ epidermotropic T cells had manifestations of a lupus-like autoimmune disorder, the significance of which warrants further investigation.
- Varga FJ, Vonderheid EC, Olbricht SM, Kadin ME. Immunohistochemical distinction of lymphomatoid papulosis and pityriasis lichenoides et varioliformis acuta. Am J Pathol. 1990;136(4):979-987.
- Erpaiboon P, Mihara I, Niimura M. Lymphomatoid papulosis: clinicopathological comparative study with pityriasis lichenoides et varioliformis acuta. J Dermatol. 1991;18(10):580-585.
- Kempf W, Kazakov DV, Palmedo G, Fraitag S, Schaerer L, Kutzner H. Pityriasis lichenoides et varioliformis acuta with numerous CD30(+) cells: a variant mimicking lymphomatoid papulosis and other cutaneous lymphomas. A clinicopathologic, immunohistochemical, and molecular biological study of 13 cases. Am J Surg Pathol. 2012;36(7):1021-1029. doi: 10.1097/PAS.0b013e31824f4f66.
- Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Haeffner AC, Stevens S, et al. Defining early mycosis fungoides. J Am Acad Dermatol. 2005;53(6):1053-1063.
- 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(3 Pt 1):559-570.
- Vonderheid EC, Kadin ME, Gocke CD. Lymphomatoid papulosis followed by pityriasis lichenoides: a common pathogenesis? Am J Dermatopathol. 2011;33(8):835-840. doi: 10.1097/DAD.0b013e3181f4d8c3.
- Ko JW, Seong JY, Suh KS, Kim ST. Pityriasis lichenoides-like mycosis fungoides in children. Br J Dermatol. 2000;142(2):347-352.
- Cho EB, Youn SH, Park EJ, Kwon IH, Kim KH, Kim KJ. CD8-positive pityriasis lichenoides-like mycosis fungoides. Eur J Dermatol. 2012;22(3):415-416. doi: 10.1684/ejd.2012.1701.
- El Shabrawi-Caelen L, Kerl H, Cerroni L. Lymphomatoid papulosis: reappraisal of clinicopathologic presentation and classification into subtypes A, B, and C. Arch Dermatol. 2004;140(4):441-447.
- Robson A, Assaf C, Bagot M, Burg G, Calonje E, Castillo C, et al. Aggressive epidermotropic cutaneous CD8+ lymphoma: a cutaneous lymphoma with distinct clinical and pathological features. Report of an EORTC Cutaneous Lymphoma Task Force Workshop. Histopathology, 2015;67(4):425-441. doi: 10.1111/his.12371.
- Tsujiwaki M, Abe R, Ohguchi Y, Hoshina D, Murata J, Fujita Y, et al. Recurrent course and CD30 expression of atypical T lymphocytes distinguish lymphomatoid papulosis from primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. Acta Derm Venereol. 2014;94(5):613-614. doi: 10.2340/00015555-1806.
- Kempf W, Kazakov DV, Schärer L,Rütten A, Mentzel T, Paredes BE, et al. Angioinvasive lymphomatoid papulosis: a new variant simulating aggressive lymphomas. Am J Surg Pathol. 2013;37(1):1-13. doi: 10.1097/PAS.0b013e3182648596.
- 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(3):444-458.
- Karai LJ, Kadin ME, Hsi ED, Sluzevich JC, Ketterling RP, Knudson RA, et al. Chromosomal rearrangements of 6p25.3 define a new subtype of lymphomatoid papulosis. Am J Surg Pathol. 2013;37(8):1173-1181. doi: 10.1097/PAS.0b013e318282d01e.
- Parekh V, Shim EH, Knapp CF 3rd, Hughey L, Elmets CA, McKay K. Primary cutaneous T-cell lymphoma with coexpression of T-cell receptors αβ and γδ. Am J Dermatopathol. 2016;38(1):66-72. doi: 10.1097/DAD.0000000000000355.
- Safai B, Incefy GS, Good RA, Dardenne M. T-cell differentiating activity in tissue cultures containing mycosis fungoides epidermal cells. N Engl J Med. 1980;303(2):113.
- Overgaard NH, Jung JW, Steptoe RJ, Wells JW. CD4+/CD8+ double-positive T cells: more than just a developmental stage? J Leukoc Biol. 2015;97(1):31-38. doi: 10.1189/jlb.1RU0814-382.
- Magro CM, Crowson AN, Harrist TJ. Atypical lymphoid infiltrates arising in cutaneous lesions of connective tissue disease. Am J Dermatopathol. 1997;19(5):446-455.
- Wu H, Telang GH, Lessin SR, Vonderheid EC. Mycosis fungoides with CD30-positive cells in the epidermis. Am J Dermatopathol. 2000;22(3):212-216.
- Reinhold U, Herpertz M, Kukel S, Oltermann I, Uerlich M, Kreysel HW. Induction of nuclear contour irregularity during T-cell activation via the T-cell receptor/CD3 complex and CD2 antigens in the presence of phorbol esters. Blood. 1994;83(3):703-706.
- Tomasini D, Tomasini CF, Cerri A, Sangalli G, Palmedo G, Hantschke M, et al. Pityriasis lichenoides: a cytotoxic T-cell-mediated skin disorder. Evidence of human parvovirus B19 DNA in nine cases. J Cutan Pathol. 2004;31(8):531-538.
- Wenzel J, Gütgemann I, Distelmaier M, Uerlich M, Mikus S, Bieber T, et al. The role of cytotoxic skin-homing CD8+ lymphocytes in cutaneous cytotoxic T-cell lymphoma and pityriasis lichenoides. J Am Acad Dermatol. 2005;53(3):422-427.
- Kim JE, Yun WJ, Mun SK, Yoon GS, Huh J, Choi JH, et al. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica: comparison of lesional T-cell subsets and investigation of viral associations. J Cutan Pathol. 2011;38(8):649-56. doi: 10.1111/j.1600-0560.2011.01717.x.
- Nelson P, Rylance P, Roden D, Trela M, Tugnet N. Viruses as potential pathogenic agents in systemic lupus erythematosus. Lupus. 2014;23(6):596-605. doi: 10.1177/0961203314531637.