EXTRAORDINARY CASE REPORT
Pediatric CD8+CD56+ Non-poikilodermatous Mycosis Fungoides: Case Report and Review of the Literature Werner Kempf, MD,* Dmitry V. Kazakov, MD, PhD,*† Sigrid M. C. Broekaert, MD,‡ and Dieter Metze, MD‡
Abstract: Mycosis fungoides (MF) displays a broad spectrum of clinical, histological, and phenotypic variants with different prognostic impact. CD8+CD56+ MF is very rare. So far, only 5 patients with CD8+CD56+ MF were reported to date. All of the previously described patients with this phenotypic variant were adults at the time of diagnosis and often manifested with widespread poikilodermatous skin lesions. Here we describe the clinicopathological features of a juvenile form of CD8+CD56+ non-poikilodermatous MF in a 10-year-old girl. In our patient, the disease displayed an indolent course and excellent prognosis with complete remission after treatment with UV light, topical steroids, and methotrexate. The differential diagnosis of CD8+ epidermotropic lymphocytic infiltrates in children is discussed, and the cases of CD8+CD56+ MF reported in the literature are reviewed. Key Words: cutaneous lymphoma, mycosis fungoides, cytotoxic lymphoma, CD56, natural killer, juvenile, pediatric, child (Am J Dermatopathol 2014;36:598–602)
INTRODUCTION Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma characterized clinically by patches and plaques and histologically by infiltrates of epidermotropic small- to medium-sized lymphocytes in patch and plaque stage. In most cases, the tumor cells manifest a mature T-helper memory phenotype (CD3+, CD4+, CD82, CD302, CD45RO+, and CD562).1–3 In recent years, several immunophenotypic variations of MF have been described, including cytotoxic forms of MF, in which neoplastic cells express CD8 and TIA-1, or CD56+ as well as double-negative forms (CD42/ CD82), dual positive (CD4+ CD8+) MF with a T-cell receptor (TCR) gd phenotype, and MF with aberrant CD20 expression.4–12 Expression of CD8+CD56+ in MF is very rare, with 5 cases reported to date, to the best of our knowledge.8,13–15 Of note, all patients with this phenotypic disease variant predominantly manifested with widespread poikilodermatous skin lesions, and all patients were adults at the time of diagnosis. From the *Kempf und Pfaltz, Histologische Diagnostik, Zürich, Switzerland; †Department of Pathology, Faculty of Medicine in Pilsen, Charles University in Prague, Prague, Czech Republic; and ‡Department of Dermatology, University of Münster, Münster, Germany. The authors declare no conflicts of interest. Reprints: Werner Kempf, MD, Kempf und Pfaltz, Histologische Diagnostik, Seminarstrasse 1, CH-8042 Zürich, Switzerland (e-mail: werner.kempf@ access.uzh.ch). © 2014 Lippincott Williams & Wilkins
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Here, we report a case of CD8+CD56+ non-poikilodermatous MF in a 10-year-old girl, review the previously reported cases, and discuss the differential diagnosis of epidermotropic infiltrates of CD8+ lymphocytes in children.
CASE REPORT A 10-year-old girl presented with widespread nonscaly erythematous to tan patches involving her trunk and, to a lesser degree, also the extremities (Fig. 1). Erythematous slightly pruritic scaly plaques had been present for 4 years. Initially, they had been located on the abdomen and spread over the whole body during the disease course. No peripheral lymphadenopathy was evident. After histological diagnosis, the patient underwent clinical staging investigations, which did not reveal extracutaneous involvement. She was treated with UVB narrow band (311 nm) resulting in partial remission. As new lesions occurred, topical steroids were applied. Later, methotrexate and systemic steroids were administered because of persistent disease, which lead to complete remission. Follow-up showed that the patient is alive and in complete remission 5 years after diagnosis.
MATERIALS AND METHODS
Tissues obtained for biopsy were fixed in 10% buffered formalin and embedded in paraffin. Hematoxylin and eosin– stained sections with a thickness of 4 mm were prepared. Immunohistochemical studies were performed on formalin-fixed paraffin-embedded tissue using the following antibodies: CD2 (1:50; Novocastra/Leica-Microsystems, Heerbrugg, Switzerland), CD3 (1:75; Dako, Glostrup, Denmark), CD4 (1:2; Novocastra/Leica-Microsystems), CD7 (1:25; Dako), CD8 (1:400; Dako), CD56 (RTU; Novocastra/Leica-Microsystems), TIA (1:50; Immunotech, Marseille, France), TCR bF1 (8A3; 1:50; Thermo Scientific, Fremont, CA), and TCR gamma (y3.20; 1:100; Thermo Scientific). Appropriate positive controls were included. TCR-g genes clonality study was performed using 3 multiplex polymerase chain reactions with different primers from the variable region in each reaction (reaction 1: Vg1–8; reaction 2: Vg9; and reaction 3: Vg10, Vg11, and Vg12) and the same Cy-5-labeled primers from the conserved region (JGP1/2, JG1/2, and JGP) as described elsewhere.16
RESULTS Histopathological Features The skin biopsy revealed a dense superficial dermal infiltrate in the upper and mid dermis, which was composed Am J Dermatopathol Volume 36, Number 7, July 2014
Am J Dermatopathol Volume 36, Number 7, July 2014
Pediatric CD8+CD56+ Mycosis Fungoides
FIGURE 1. Multiple erythematous to tan patches mainly involving the chest wall, abdomen, lower back, and buttocks (A, B). Close-up of the lesions (C).
of small lymphoid cells. A marked epidermotropism with prominent lining-up of small lymphocytes in the basal layer of the epidermis were discerned (Fig. 2). The lymphocytes, particularly the intraepidermal lymphocytes exhibited nuclear atypia. There were also discrete foci of vacuolization at the dermo–epidermal junction and areas of parakeratosis.
Immunohistochemical Findings The neoplastic cells coexpressed CD8 and CD56 (90% of the intraepidermal cells), with CD8+ cells located both in the epidermis and the dermis, whereas the CD56+ lymphocytic component was mainly restricted to the basal layer of the epidermis. Approximately 90% of the intraepidermal lymphocytes were positive for TIA-1 (Fig. 3). All intraepidermal and dermal lymphocytes expressed CD2 and bF1 (TCR a/b). CD4 was expressed by less than 10% of intraepidermal and 60% of the dermal lymphocytes. Less than 10% of all lymphocytes were positive for CD30. Expression of TCR gamma was not observed.
Molecular Biological Findings
Monoclonal (double clonal) TCR-g gene rearrangement was identified by polymerase chain reaction.
Ó 2014 Lippincott Williams & Wilkins
DISCUSSION MF usually occurs in adults in their sixth to seventh decade but may occasionally affect children.17,18 Juvenile onset MF is often characterized by CD8 expression and hypopigmented or hyperpigmented skin lesions19,20 Less common are other rare and “atypical” MF variants, including ichthyosiform, follicular, poikilodermic, and unilesional or solitary MF.21–23 Exquisitely rare in MF children is a combination of 2 atypical disease forms. Our case is the second pediatric case of CD8+CD56+ MF. A 20-year-old patient with an identical immunophenotype was reported by Shiomi et al.15 This patient had a 10-year history of the disease and presented with generalized poikilodermatous lesions. In contrast, our patient manifested with erythematous and slightly tan non-poikilodermatous patches. Of note, of the 5 cases of CD8+CD56+ MF reported to date, all individuals were female and 5 manifested with poikilodermatous skin lesions, suggesting a proclivity of this particular immunophenotype with poikilodermatous clinical features and the female gender (Table 1). It seems that poikilodermatous MF is not uncommonly associated with a cytotoxic phenotype—a predominance of CD8+ atypical cells was detected in 15 of 40 cases of poikilodermic MF in a series described by Abbott et al.24 Apart from MF, CD8+CD56+ neoplastic cells have been www.amjdermatopathology.com |
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FIGURE 2. Epidermotropic infiltrate (A) composed of small lymphocytes with marked epidermotropism (B) and lining-up of the neoplastic cells in the basal layer of the epidermis (C).
reported in a case of erythrodermic cutaneous T-cell lymphoma.25 In their patient, the disease had started at the age of 18 and manifested with erythrodermic and poikilodermatous eruptions with circulating malignant T cells. It remains unclarified whether this case represents erythrodermic MF with leukemic spread of tumor cells or Sézary syndrome. Previous studies demonstrated that neither CD56 nor CD8 expression in MF portent a worse prognosis.26,27
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FIGURE 3. The cells are immunoreactive for CD8 (A), CD56 (B), and TIA-1 (C). Note that CD56 reactivity is mainly restricted to the intraepidermal lymphocytes, whereas CD8 is expressed by the intraepidermal and dermal cells.
However, expression of either marker requires the differential diagnosis with other cytotoxic and natural killer lymphomas.28–32 Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (CD8+ AECTCL) is the main differential diagnostic consideration from the histopathological viewpoint. In this condition, epidermotropism and nuclear pleomorphism are more prominent and often accompanied by Ó 2014 Lippincott Williams & Wilkins
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TABLE 1. Main Clinical Features of the Reported Cases of CD8+ CD56+ MF Sex/Age at Diagnosis
History
Clinical Features
Treatment
Response and Follow-up
Reference
Case 1
F/45
5 yrs
Local RT, TS
PR, 18 mo
Wain et al13
Case Case Case Case Case
F/37 F/58 F/68 F/20 F/10
5 yrs 15 yrs 20 yrs 10 yrs 4 yrs
Progressive poikiloderma, hypopigmented lesions Generalized poikiloderma, tumor Poikiloderma, hyperpigmented lesions Poikiloderma Generalized poikiloderma Generalized patches
PUVA, excision PUVA NB-UVB, PUVA TS UVB, TS, SS, MTX
CR, 24 mo NA CR, 6 mo PR, NA CR, 5 yrs
Wain et al13 Nikolaou et al14 Sawada et al8 Shiomi et al15 Present case
Case
2 3 4 5 6
CR, complete remission; MTX, methotrexate; NA, not available; NB-UVB, Narrowband UVB; PR, partial remission; PUVA, Psoralen UVA; RT, radiation therapy; TS, topical steroids; SS, systemic steroids.
necrotic keratinocytes and erosion. Clinically, the patches, plaques, and nodules rapidly develop and often show erosion and ulceration. The disease runs an aggressive course with a median survival of 32 months.33 In our patient, the clinical presentation with non-erosive patches and an indolent course correspond to that of MF. Lymphomatoid papulosis (LyP) type D is a recently described new variant of LyP characterized by epidermotropic infiltrates of small- to medium-sized CD8+ and CD30+ T cells, which histologically simulates CD8+ AECTCL.34 Clinical presentation with waxing and waning papulonodular lesions undergoing spontaneous regression of individual lesions within a few weeks allows distinguishing LyP type D from CD8+CD56+ MF as well as from CD8+ AECTCL. Pityriasis lichenoides et varioliformis acuta presents with epidermotropic CD8+ and CD30+ lymphocytic infiltrates, which histologically mimic CD8+ MF, LyP type D, and CD8+ AECTCL.35 The clinical presentation, however, easily distinguishes between these lymphoproliferative disorders. In conclusion, we report a case of pediatric CD8+CD56+ non-poikilodermatous MF. Based on the indolent course in our patient and the previously reported patients, expression of CD8+ and CD56+ by tumor cells in MF does not seem to be linked to an aggressive course. Dermatologists and dermatopathologists should be aware of this rare MF variant to avoid unnecessarily aggressive treatment and to distinguish this disease variant from its differential diagnoses. REFERENCES 1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768–3785. 2. Burg G, Kempf W, Cozzio A, et al. WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects. J Cutan Pathol. 2005;32:647–674. 3. Ralfkiaer E, Wantzin GL, Mason DY, et al. Phenotypic characterization of lymphocyte subsets in mycosis fungoides. Comparison with large plaque parapsoriasis and benign chronic dermatoses. Am J Clin Pathol. 1985;84:610–619. 4. Klekotka PA, Faulkner-Jones B, Heffernan MP. A case of CD56+ mycosis fungoides. Arch Dermatol. 2006;142:1370–1372. 5. Hodak E, David M, Maron L, et al. CD4/CD8 double-negative epidermotropic cutaneous T-cell lymphoma: an immunohistochemical variant of mycosis fungoides. J Am Acad Dermatol. 2006;55:276–284. 6. Sen F, Kang S, Cangiarella J, et al. CD20 positive mycosis fungoides: a case report. J Cutan Pathol. 2008;35:398–403. 7. Horst BA, Kasper R, LeBoit PE. CD4+, CD56+ mycosis fungoides: case report and review of the literature. Am J Dermatopathol. 2009;31:74–76.
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8. Sawada Y, Sugita K, Kabashima R, et al. CD8+ CD56+ mycosis fungoides with an indolent clinical behaviour: case report and literature review. Acta Derm Venereol. 2010;90:525–526. 9. Knapp CF, Mathew R, Messina JL, et al. CD4/CD8 dual-positive mycosis fungoides: a previously unrecognized variant. Am J Dermatopathol. 2012;34:e37–e39. 10. Kempf W, Kazakov DV, Cipolat C, et al. CD4/CD8 double negative mycosis fungoides with PD-1 (CD279) expression—a disease of follicular helper T-cells? Am J Dermatopathol. 2012;34:757–761. 11. Guitart J, Weisenburger DD, Subtil A, et al. Cutaneous gammadelta T-cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas. Am J Surg Pathol. 2012;36:1656–1665. 12. Rodriguez-Pinilla SM, Ortiz-Romero PL, Monsalvez V, et al. TCRgamma expression in primary cutaneous T-cell lymphomas. Am J Surg Pathol. 2013;37:375–384. 13. Wain EM, Orchard GE, Mayou S, et al. Mycosis fungoides with a CD56+ immunophenotype. J Am Acad Dermatol. 2005;53:158–163. 14. Nikolaou VA, Papadavid E, Katsambas A, et al. Clinical characteristics and course of CD8+ cytotoxic variant of mycosis fungoides: a case series of seven patients. Br J Dermatol. 2009;161:826–830. 15. Shiomi T, Monobe Y, Kuwabara C, et al. Poikilodermatous mycosis fungoides with a CD8+ CD56+ immunophenotype: a case report and literature review. J Cutan Pathol. 2012;40:317–320. 16. Kneba M, Bolz I, Linke B, et al. Characterization of clone-specific rearrangement T-cell receptor gamma-chain genes in lymphomas and leukemias by the polymerase chain reaction and DNA sequencing. Blood. 1994;84:574–581. 17. Koch SE, Zackheim HS, Williams ML, et al. Mycosis fungoides beginning in childhood and adolescence. J Am Acad Dermatol. 1987;17:563–570. 18. Crowley JJ, Nikko A, Varghese A, et al. Mycosis fungoides in young patients: clinical characteristics and outcome. J Am Acad Dermatol. 1998;38:696–701. 19. Whittam LR, Calonje E, Orchard G, et al. CD8-positive juvenile onset mycosis fungoides: an immunohistochemical and genotypic analysis of six cases. Br J Dermatol. 2000;143:1199–1204. 20. El-Shabrawi-Caelen L, Cerroni L, Medeiros LJ, et al. Hypopigmented mycosis fungoides: frequent expression of a CD8+ T-cell phenotype. Am J Surg Pathol. 2002;26:450–457. 21. Hodak E, David M. Follicular mycosis fungoides. J Cutan Pathol. 2002; 29:625. 22. Hodak E, Amitay I, Feinmesser M, et al. Ichthyosiform mycosis fungoides: an atypical variant of cutaneous T-cell lymphoma. J Am Acad Dermatol. 2004;50:368–374. 23. Kazakov DV, Burg G, Kempf W. Clinicopathological spectrum of mycosis fungoides. J Eur Acad Dermatol Venereol. 2004;18:397–415. 24. Abbott RA, Sahni D, Robson A, et al. Poikilodermatous mycosis fungoides: a study of its clinicopathological, immunophenotypic, and prognostic features. J Am Acad Dermatol. 2011;65:313–319. 25. Ohshima A, Tokura Y, Misawa J, et al. Erythrodermic cutaneous T-cell lymphoma with CD8+CD56+ leukaemic T cells in a young woman. Br J Dermatol. 2003;149:891–893. 26. Dummer R, Kamarashev J, Kempf W, et al. Junctional CD8+ cutaneous lymphomas with nonaggressive clinical behavior: a CD8+ variant of mycosis fungoides? Arch Dermatol. 2002;138:199–203.
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27. Massone C, Crisman G, Kerl H, et al. The prognosis of early mycosis fungoides is not influenced by phenotype and T-cell clonality. Br J Dermatol. 2008;159:881–886. 28. Agnarsson BA, Vonderheid EC, Kadin ME. CD8+ cutaneous T-cell lymphoma. Am J Dermatopathol. 1991;13:628–629. 29. Lu D, Patel KA, Duvic M, et al. Clinical and pathological spectrum of CD8-positive cutaneous T-cell lymphomas. J Cutan Pathol. 2002;29: 465–472. 30. Santucci M, Pimpinelli N, Massi D, et al. Cytotoxic/natural killer cell cutaneous lymphomas. Report of EORTC Cutaneous Lymphoma Task Force Workshop. Cancer. 2003;97:610–627. 31. Massone C, Chott A, Metze D, et al. Subcutaneous, blastic natural killer (NK), NK/T-cell, and other cytotoxic lymphomas of the skin: a morphologic, immunophenotypic, and molecular study of 50 patients. Am J Surg Pathol. 2004;28:719–735.
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32. Diwan H, Ivan D. CD8-positive mycosis fungoides and primary cutaneous aggressive epidermotropic CD8-positive cytotoxic T-cell lymphoma. J Cutan Pathol. 2009;36:390–392. 33. Berti E, Tomasini D, Vermeer MH, et al. Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphomas. A distinct clinicopathological entity with an aggressive clinical behavior. Am J Pathol. 1999;155:483–492. 34. Saggini A, Gulia A, Argenyi Z, et al. A variant of lymphomatoid papulosis simulating primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. Description of 9 cases. Am J Surg Pathol. 2010;34:1168–1175. 35. Kempf W, Kazakov DV, Palmedo G, et al. 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;36:1021–1029.
Ó 2014 Lippincott Williams & Wilkins
Pediatric CD8+CD56+ Non-poikilodermatous Mycosis Fungoides: Case Report and Review of the Literature Werner Kempf, MD,* Dmitry V. Kazakov, MD, PhD,*† Sigrid M. C. Broekaert, MD,‡ and Dieter Metze, MD‡
Abstract: Mycosis fungoides (MF) displays a broad spectrum of clinical, histological, and phenotypic variants with different prognostic impact. CD8+CD56+ MF is very rare. So far, only 5 patients with CD8+CD56+ MF were reported to date. All of the previously described patients with this phenotypic variant were adults at the time of diagnosis and often manifested with widespread poikilodermatous skin lesions. Here we describe the clinicopathological features of a juvenile form of CD8+CD56+ non-poikilodermatous MF in a 10-year-old girl. In our patient, the disease displayed an indolent course and excellent prognosis with complete remission after treatment with UV light, topical steroids, and methotrexate. The differential diagnosis of CD8+ epidermotropic lymphocytic infiltrates in children is discussed, and the cases of CD8+CD56+ MF reported in the literature are reviewed. Key Words: cutaneous lymphoma, mycosis fungoides, cytotoxic lymphoma, CD56, natural killer, juvenile, pediatric, child (Am J Dermatopathol 2014;36:598–602)
INTRODUCTION Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma characterized clinically by patches and plaques and histologically by infiltrates of epidermotropic small- to medium-sized lymphocytes in patch and plaque stage. In most cases, the tumor cells manifest a mature T-helper memory phenotype (CD3+, CD4+, CD82, CD302, CD45RO+, and CD562).1–3 In recent years, several immunophenotypic variations of MF have been described, including cytotoxic forms of MF, in which neoplastic cells express CD8 and TIA-1, or CD56+ as well as double-negative forms (CD42/ CD82), dual positive (CD4+ CD8+) MF with a T-cell receptor (TCR) gd phenotype, and MF with aberrant CD20 expression.4–12 Expression of CD8+CD56+ in MF is very rare, with 5 cases reported to date, to the best of our knowledge.8,13–15 Of note, all patients with this phenotypic disease variant predominantly manifested with widespread poikilodermatous skin lesions, and all patients were adults at the time of diagnosis. From the *Kempf und Pfaltz, Histologische Diagnostik, Zürich, Switzerland; †Department of Pathology, Faculty of Medicine in Pilsen, Charles University in Prague, Prague, Czech Republic; and ‡Department of Dermatology, University of Münster, Münster, Germany. The authors declare no conflicts of interest. Reprints: Werner Kempf, MD, Kempf und Pfaltz, Histologische Diagnostik, Seminarstrasse 1, CH-8042 Zürich, Switzerland (e-mail: werner.kempf@ access.uzh.ch). © 2014 Lippincott Williams & Wilkins
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Here, we report a case of CD8+CD56+ non-poikilodermatous MF in a 10-year-old girl, review the previously reported cases, and discuss the differential diagnosis of epidermotropic infiltrates of CD8+ lymphocytes in children.
CASE REPORT A 10-year-old girl presented with widespread nonscaly erythematous to tan patches involving her trunk and, to a lesser degree, also the extremities (Fig. 1). Erythematous slightly pruritic scaly plaques had been present for 4 years. Initially, they had been located on the abdomen and spread over the whole body during the disease course. No peripheral lymphadenopathy was evident. After histological diagnosis, the patient underwent clinical staging investigations, which did not reveal extracutaneous involvement. She was treated with UVB narrow band (311 nm) resulting in partial remission. As new lesions occurred, topical steroids were applied. Later, methotrexate and systemic steroids were administered because of persistent disease, which lead to complete remission. Follow-up showed that the patient is alive and in complete remission 5 years after diagnosis.
MATERIALS AND METHODS
Tissues obtained for biopsy were fixed in 10% buffered formalin and embedded in paraffin. Hematoxylin and eosin– stained sections with a thickness of 4 mm were prepared. Immunohistochemical studies were performed on formalin-fixed paraffin-embedded tissue using the following antibodies: CD2 (1:50; Novocastra/Leica-Microsystems, Heerbrugg, Switzerland), CD3 (1:75; Dako, Glostrup, Denmark), CD4 (1:2; Novocastra/Leica-Microsystems), CD7 (1:25; Dako), CD8 (1:400; Dako), CD56 (RTU; Novocastra/Leica-Microsystems), TIA (1:50; Immunotech, Marseille, France), TCR bF1 (8A3; 1:50; Thermo Scientific, Fremont, CA), and TCR gamma (y3.20; 1:100; Thermo Scientific). Appropriate positive controls were included. TCR-g genes clonality study was performed using 3 multiplex polymerase chain reactions with different primers from the variable region in each reaction (reaction 1: Vg1–8; reaction 2: Vg9; and reaction 3: Vg10, Vg11, and Vg12) and the same Cy-5-labeled primers from the conserved region (JGP1/2, JG1/2, and JGP) as described elsewhere.16
RESULTS Histopathological Features The skin biopsy revealed a dense superficial dermal infiltrate in the upper and mid dermis, which was composed Am J Dermatopathol Volume 36, Number 7, July 2014
Am J Dermatopathol Volume 36, Number 7, July 2014
Pediatric CD8+CD56+ Mycosis Fungoides
FIGURE 1. Multiple erythematous to tan patches mainly involving the chest wall, abdomen, lower back, and buttocks (A, B). Close-up of the lesions (C).
of small lymphoid cells. A marked epidermotropism with prominent lining-up of small lymphocytes in the basal layer of the epidermis were discerned (Fig. 2). The lymphocytes, particularly the intraepidermal lymphocytes exhibited nuclear atypia. There were also discrete foci of vacuolization at the dermo–epidermal junction and areas of parakeratosis.
Immunohistochemical Findings The neoplastic cells coexpressed CD8 and CD56 (90% of the intraepidermal cells), with CD8+ cells located both in the epidermis and the dermis, whereas the CD56+ lymphocytic component was mainly restricted to the basal layer of the epidermis. Approximately 90% of the intraepidermal lymphocytes were positive for TIA-1 (Fig. 3). All intraepidermal and dermal lymphocytes expressed CD2 and bF1 (TCR a/b). CD4 was expressed by less than 10% of intraepidermal and 60% of the dermal lymphocytes. Less than 10% of all lymphocytes were positive for CD30. Expression of TCR gamma was not observed.
Molecular Biological Findings
Monoclonal (double clonal) TCR-g gene rearrangement was identified by polymerase chain reaction.
Ó 2014 Lippincott Williams & Wilkins
DISCUSSION MF usually occurs in adults in their sixth to seventh decade but may occasionally affect children.17,18 Juvenile onset MF is often characterized by CD8 expression and hypopigmented or hyperpigmented skin lesions19,20 Less common are other rare and “atypical” MF variants, including ichthyosiform, follicular, poikilodermic, and unilesional or solitary MF.21–23 Exquisitely rare in MF children is a combination of 2 atypical disease forms. Our case is the second pediatric case of CD8+CD56+ MF. A 20-year-old patient with an identical immunophenotype was reported by Shiomi et al.15 This patient had a 10-year history of the disease and presented with generalized poikilodermatous lesions. In contrast, our patient manifested with erythematous and slightly tan non-poikilodermatous patches. Of note, of the 5 cases of CD8+CD56+ MF reported to date, all individuals were female and 5 manifested with poikilodermatous skin lesions, suggesting a proclivity of this particular immunophenotype with poikilodermatous clinical features and the female gender (Table 1). It seems that poikilodermatous MF is not uncommonly associated with a cytotoxic phenotype—a predominance of CD8+ atypical cells was detected in 15 of 40 cases of poikilodermic MF in a series described by Abbott et al.24 Apart from MF, CD8+CD56+ neoplastic cells have been www.amjdermatopathology.com |
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Kempf et al
FIGURE 2. Epidermotropic infiltrate (A) composed of small lymphocytes with marked epidermotropism (B) and lining-up of the neoplastic cells in the basal layer of the epidermis (C).
reported in a case of erythrodermic cutaneous T-cell lymphoma.25 In their patient, the disease had started at the age of 18 and manifested with erythrodermic and poikilodermatous eruptions with circulating malignant T cells. It remains unclarified whether this case represents erythrodermic MF with leukemic spread of tumor cells or Sézary syndrome. Previous studies demonstrated that neither CD56 nor CD8 expression in MF portent a worse prognosis.26,27
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FIGURE 3. The cells are immunoreactive for CD8 (A), CD56 (B), and TIA-1 (C). Note that CD56 reactivity is mainly restricted to the intraepidermal lymphocytes, whereas CD8 is expressed by the intraepidermal and dermal cells.
However, expression of either marker requires the differential diagnosis with other cytotoxic and natural killer lymphomas.28–32 Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (CD8+ AECTCL) is the main differential diagnostic consideration from the histopathological viewpoint. In this condition, epidermotropism and nuclear pleomorphism are more prominent and often accompanied by Ó 2014 Lippincott Williams & Wilkins
Am J Dermatopathol Volume 36, Number 7, July 2014
Pediatric CD8+CD56+ Mycosis Fungoides
TABLE 1. Main Clinical Features of the Reported Cases of CD8+ CD56+ MF Sex/Age at Diagnosis
History
Clinical Features
Treatment
Response and Follow-up
Reference
Case 1
F/45
5 yrs
Local RT, TS
PR, 18 mo
Wain et al13
Case Case Case Case Case
F/37 F/58 F/68 F/20 F/10
5 yrs 15 yrs 20 yrs 10 yrs 4 yrs
Progressive poikiloderma, hypopigmented lesions Generalized poikiloderma, tumor Poikiloderma, hyperpigmented lesions Poikiloderma Generalized poikiloderma Generalized patches
PUVA, excision PUVA NB-UVB, PUVA TS UVB, TS, SS, MTX
CR, 24 mo NA CR, 6 mo PR, NA CR, 5 yrs
Wain et al13 Nikolaou et al14 Sawada et al8 Shiomi et al15 Present case
Case
2 3 4 5 6
CR, complete remission; MTX, methotrexate; NA, not available; NB-UVB, Narrowband UVB; PR, partial remission; PUVA, Psoralen UVA; RT, radiation therapy; TS, topical steroids; SS, systemic steroids.
necrotic keratinocytes and erosion. Clinically, the patches, plaques, and nodules rapidly develop and often show erosion and ulceration. The disease runs an aggressive course with a median survival of 32 months.33 In our patient, the clinical presentation with non-erosive patches and an indolent course correspond to that of MF. Lymphomatoid papulosis (LyP) type D is a recently described new variant of LyP characterized by epidermotropic infiltrates of small- to medium-sized CD8+ and CD30+ T cells, which histologically simulates CD8+ AECTCL.34 Clinical presentation with waxing and waning papulonodular lesions undergoing spontaneous regression of individual lesions within a few weeks allows distinguishing LyP type D from CD8+CD56+ MF as well as from CD8+ AECTCL. Pityriasis lichenoides et varioliformis acuta presents with epidermotropic CD8+ and CD30+ lymphocytic infiltrates, which histologically mimic CD8+ MF, LyP type D, and CD8+ AECTCL.35 The clinical presentation, however, easily distinguishes between these lymphoproliferative disorders. In conclusion, we report a case of pediatric CD8+CD56+ non-poikilodermatous MF. Based on the indolent course in our patient and the previously reported patients, expression of CD8+ and CD56+ by tumor cells in MF does not seem to be linked to an aggressive course. Dermatologists and dermatopathologists should be aware of this rare MF variant to avoid unnecessarily aggressive treatment and to distinguish this disease variant from its differential diagnoses. REFERENCES 1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105:3768–3785. 2. Burg G, Kempf W, Cozzio A, et al. WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects. J Cutan Pathol. 2005;32:647–674. 3. Ralfkiaer E, Wantzin GL, Mason DY, et al. Phenotypic characterization of lymphocyte subsets in mycosis fungoides. Comparison with large plaque parapsoriasis and benign chronic dermatoses. Am J Clin Pathol. 1985;84:610–619. 4. Klekotka PA, Faulkner-Jones B, Heffernan MP. A case of CD56+ mycosis fungoides. Arch Dermatol. 2006;142:1370–1372. 5. Hodak E, David M, Maron L, et al. CD4/CD8 double-negative epidermotropic cutaneous T-cell lymphoma: an immunohistochemical variant of mycosis fungoides. J Am Acad Dermatol. 2006;55:276–284. 6. Sen F, Kang S, Cangiarella J, et al. CD20 positive mycosis fungoides: a case report. J Cutan Pathol. 2008;35:398–403. 7. Horst BA, Kasper R, LeBoit PE. CD4+, CD56+ mycosis fungoides: case report and review of the literature. Am J Dermatopathol. 2009;31:74–76.
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8. Sawada Y, Sugita K, Kabashima R, et al. CD8+ CD56+ mycosis fungoides with an indolent clinical behaviour: case report and literature review. Acta Derm Venereol. 2010;90:525–526. 9. Knapp CF, Mathew R, Messina JL, et al. CD4/CD8 dual-positive mycosis fungoides: a previously unrecognized variant. Am J Dermatopathol. 2012;34:e37–e39. 10. Kempf W, Kazakov DV, Cipolat C, et al. CD4/CD8 double negative mycosis fungoides with PD-1 (CD279) expression—a disease of follicular helper T-cells? Am J Dermatopathol. 2012;34:757–761. 11. Guitart J, Weisenburger DD, Subtil A, et al. Cutaneous gammadelta T-cell lymphomas: a spectrum of presentations with overlap with other cytotoxic lymphomas. Am J Surg Pathol. 2012;36:1656–1665. 12. Rodriguez-Pinilla SM, Ortiz-Romero PL, Monsalvez V, et al. TCRgamma expression in primary cutaneous T-cell lymphomas. Am J Surg Pathol. 2013;37:375–384. 13. Wain EM, Orchard GE, Mayou S, et al. Mycosis fungoides with a CD56+ immunophenotype. J Am Acad Dermatol. 2005;53:158–163. 14. Nikolaou VA, Papadavid E, Katsambas A, et al. Clinical characteristics and course of CD8+ cytotoxic variant of mycosis fungoides: a case series of seven patients. Br J Dermatol. 2009;161:826–830. 15. Shiomi T, Monobe Y, Kuwabara C, et al. Poikilodermatous mycosis fungoides with a CD8+ CD56+ immunophenotype: a case report and literature review. J Cutan Pathol. 2012;40:317–320. 16. Kneba M, Bolz I, Linke B, et al. Characterization of clone-specific rearrangement T-cell receptor gamma-chain genes in lymphomas and leukemias by the polymerase chain reaction and DNA sequencing. Blood. 1994;84:574–581. 17. Koch SE, Zackheim HS, Williams ML, et al. Mycosis fungoides beginning in childhood and adolescence. J Am Acad Dermatol. 1987;17:563–570. 18. Crowley JJ, Nikko A, Varghese A, et al. Mycosis fungoides in young patients: clinical characteristics and outcome. J Am Acad Dermatol. 1998;38:696–701. 19. Whittam LR, Calonje E, Orchard G, et al. CD8-positive juvenile onset mycosis fungoides: an immunohistochemical and genotypic analysis of six cases. Br J Dermatol. 2000;143:1199–1204. 20. El-Shabrawi-Caelen L, Cerroni L, Medeiros LJ, et al. Hypopigmented mycosis fungoides: frequent expression of a CD8+ T-cell phenotype. Am J Surg Pathol. 2002;26:450–457. 21. Hodak E, David M. Follicular mycosis fungoides. J Cutan Pathol. 2002; 29:625. 22. Hodak E, Amitay I, Feinmesser M, et al. Ichthyosiform mycosis fungoides: an atypical variant of cutaneous T-cell lymphoma. J Am Acad Dermatol. 2004;50:368–374. 23. Kazakov DV, Burg G, Kempf W. Clinicopathological spectrum of mycosis fungoides. J Eur Acad Dermatol Venereol. 2004;18:397–415. 24. Abbott RA, Sahni D, Robson A, et al. Poikilodermatous mycosis fungoides: a study of its clinicopathological, immunophenotypic, and prognostic features. J Am Acad Dermatol. 2011;65:313–319. 25. Ohshima A, Tokura Y, Misawa J, et al. Erythrodermic cutaneous T-cell lymphoma with CD8+CD56+ leukaemic T cells in a young woman. Br J Dermatol. 2003;149:891–893. 26. Dummer R, Kamarashev J, Kempf W, et al. Junctional CD8+ cutaneous lymphomas with nonaggressive clinical behavior: a CD8+ variant of mycosis fungoides? Arch Dermatol. 2002;138:199–203.
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32. Diwan H, Ivan D. CD8-positive mycosis fungoides and primary cutaneous aggressive epidermotropic CD8-positive cytotoxic T-cell lymphoma. J Cutan Pathol. 2009;36:390–392. 33. Berti E, Tomasini D, Vermeer MH, et al. Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphomas. A distinct clinicopathological entity with an aggressive clinical behavior. Am J Pathol. 1999;155:483–492. 34. Saggini A, Gulia A, Argenyi Z, et al. A variant of lymphomatoid papulosis simulating primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. Description of 9 cases. Am J Surg Pathol. 2010;34:1168–1175. 35. Kempf W, Kazakov DV, Palmedo G, et al. 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;36:1021–1029.
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