BJD
British Journal of Dermatology
CASE REPORT
Primary cutaneous T-cell lymphoma presenting as mycosis fungoides with a T-/null-cell phenotype: report of two cases L. Bekel,1 G. Chaby,1 C. Lok,1 A. Dadban,1 D. Chatelain,2 S. Ingen-Housz-Oro3 and N. Ortonne4 1
Department Department 3 Department 4 Department 2
of of of of
Dermatology, H^opital Sud, University of Amiens, 80054 Amiens, France Pathology, H^opital Nord, University of Amiens, 80054 Amiens, France Dermatology, Assistance Publique-H^opitaux de Paris (AP-HP) Groupe Hospitalier Henri Mondor, UPEC University, 94010 Creteil, France Pathology, INSERM U955 Equipe 9, AP-HP, Groupe Hospitalier Henri Mondor, UPEC University, 94010 Creteil, France
Summary Correspondence Lilia Bekel. E-mail: [email protected]
Accepted for publication 9 November 2014
Variations in the clinical and histological presentation of cutaneous T-cell lymphoma (CTCL) can hamper diagnosis. We report two cases of a novel presentation of CTCL characterized by an aberrant immunophenotype with complete loss of pan T-cell antigens including T-cell receptor b chain and showing the clinical and histopathological appearance of erythrodermic and plaque-stage mycosis fungoides.
Funding sources None.
Conflicts of interest None declared. DOI 10.1111/bjd.13563
What’s already known about this topic?
• •
Phenotypic aberrations with loss of some surface antigens are common findings in malignant cutaneous T-cell lymphomas. The almost complete absence of T-cell marker expression in mycosis fungoides has never been reported previously.
What does this study add?
• •
We describe two original observations of cutaneous T-cell lymphoma characterized by an aberrant immunophenotype with loss of pan T-cell antigens including the Tcell receptor b chain. Lymphoma behaviour and evolution does not appear to be modified in these cases.
Cutaneous T-cell lymphoma (CTCL) diagnosis is based on clinical, histological, immunophenotypic and molecular grounds.1,2 The neoplastic cells in mycosis fungoides (MF) usually have a mature CD2+, CD3+, CD4+, CD5+, CD45RO+ and CD8 memory T-cell phenotype.1,2 If phenotypic aberrations with loss of some surface antigens are common findings in CTCL,2–5 the absence of pan-T antigens is rare especially in MF.4,5 We describe two original observations of unusual MF characterized by an aberrant immunophenotype with a complete loss of pan T-cell antigens.
Case report 1
© 2014 British Association of Dermatologists
British Journal of Dermatology (2015) 172, pp1637–1641
A 57-year-old man presented with recurrent episodes of pyoderma gangrenosum of the lower limbs, confirmed by skin biopsies, but the initial staging did not reveal associated underlying disease. Five years later, in December 2007, he presented with an erythroderma with peripheral lymphadenopathy and nodules on the dorsal face of the left foot and the inner side of the right limb (Fig. 1a,b). 1637
1638 Aberrant immunophenotypes in mycosis fungoides, L. Bekel et al.
(a)
(b)
(c)
Fig 1. Clinical presentation. (a) Case 1. Erythroderma of the back. (b) Case 1. Nodular lesion of the right calf. (c) Case 2. Erythematosquamous plaque on the left part of the chest.
The histopathology of both the erythrodermic skin and the nodules revealed similar lesions, with more pronounced features in the nodular lesions. They showed a subepidermal band-like lymphocytic infiltrate with marked epidermotropism associated with diffuse and interstitial infiltration of the dermis. The infiltrate was monomorphic, being composed of slightly atypical lymphocytes with hyperchromatic nuclei, sometimes grouped in clusters and forming Pautrier’s microabscesses within the epidermis (Fig. 2). Immunophenotyping showed that the neoplastic T-cells were negative for all T-cell antigens investigated (CD2, CD3, CD4, CD5, CD7, CD8). Immunostaining for TdT, CD99, CD56, CD25, JUNB and p80/ ALK-1, for cytotoxic markers (granzyme B and TiA1), follicular helper T-cell markers (PD1/CD279, ICOS/CD278 and CD10) and the histiocytic markers CD1a, CD163 were all negative, whereas neoplastic cells strongly expressed CD45 and CD30 (Fig. 2). The Sezary cell marker CD158k (KIR3DL2) was also negative. Interestingly, no T-cell receptor (TCR) b and c chain expression could be demonstrated using immunohistochemistry. Polymerase chain reaction to assess clonality at the TCRc locus demonstrated a dominant T-cell clone in the skin and an oligoclonal pattern in the blood. Full blood cell count was normal with absence of Sezary cells, and the CD4/CD8 ratio was 2.5. Human T-cell lymphotrophic virus and Epstein–Barr virus serological tests were negative. Additionally, a biopsy of a lymphadenopathy was performed and showed only a reactional histological appearance. Thoracic-abdominal-pelvic computed tomography was normal. The diagnosis of stage III MF T4N1M0 [World Health Organization–European Organisation for Research and Treatment of Cancer (WHO–EORTC)] was retained after multidisciplinary consultation and clinicopathological confirmation. The patient responded very well to a combination of daily oral prednisone 10 mg and methotrexate 25 mg weekly. This led to clinical and histological remission. The onset 2 years later of interstitial lung disease required treatment by interferon (3 million units three times per week) and then successive therapeutic changes due to failures: topical carmustine (three British Journal of Dermatology (2015) 172, pp1637–1641
times per week), chlormethine (three times per week) and bexarotene (300 mg m 2). The latter was started 10 months ago with good efficiency to date.
Case report 2 A 71-year-old man presented with erythematous, scaly, noninfiltrated plaques on the limbs and trunk for several months (Fig. 1c). There was no peripheral lymphadenopathy. In May 2013, a skin biopsy showed the appearance of epidermotropic cutaneous T-cell lymphoma. The epidermotropic component consisted of atypical small lymphocytes showing hyperchromatic nuclei aligned along the basement membrane zone (Fig. 2b). Interestingly, using immunohistochemistry, we observed a phenotype similar to that in case 1, with a loss of pan T-cell markers (TCRb and c, CD2, CD3, CD4, CD5, CD7 and CD8). As in case 1, epidermotropic neoplastic cells expressed CD45 and CD30 (Fig. 2) while CD158k/KIR3DL2 was not expressed. All the other markers were negative (TdT, CD99, CD56, CD25, JUNB, p80/ALK-1, granzyme B, TiA1, PD1/CD279, ICOS/CD278, CXCL13 CD10, CD1a and CD163). No TCRc gene rearrangement was detected by polymerase chain reaction in skin or in blood. Blood cell count (including Sezary cells) and computed tomography of the whole body was normal. Stage IA MF T1bN0M0 according to the EORTC–WHO classification was diagnosed. After treatment with topical corticosteroids (clobetasol 0.05%), cutaneous plaques regressed completely.
Discussion The clinical and histological presentation of CTCL is variable so the diagnosis may be challenging and require clinicopathological confirmation. In the cases we observed, clinical and histological features were those of a CTCL. To our knowledge, the almost complete absence of T-cell markers expression in MF has never previously been reported in the literature. The presence of T-reactive cells usually associated with neoplastic T-cells in the MF infiltrates © 2014 British Association of Dermatologists
Aberrant immunophenotypes in mycosis fungoides, L. Bekel et al. 1639
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(i)
(j)
Fig 2. Histopathology and phenotype: representative pictures of case 1 are presented on the left and pictures of case 2 are shown on the right. (a) Case 1: the lymphoma presented with a band-like subepidermal epidermotropic lymphocytic infiltrate made of atypical small lymphocytes with hyperchromatic nuclei, often grouped in clusters (Pautrier’s microabscesses) in the epidermis. (b) Case 2: the epidermotropic component was more subtle, made of small atypical lymphocytes with hyperchromatic nuclei aligned along the basement membrane. (c) TCRb negativity in case 1. (d) All neoplastic cells expressed CD30 in case 1. (e, f) CD45 and CD30 positivity in case 2. (g, h) Negativity CD4 and CD8 staining in case 1. (i, j) Negative staining for CD3 and CD5 in case 2. Arrows show epidermotropic lymphocytes grouped in Pautrier’s microabscesses, and arrowheads show neoplastic lymphocytes aligned along the basement membrane. (a, b) Haematoxylin and eosin stain; (c–j) immunostaining revealed by diaminobenzidine. Original magnifications: a, b, c, i, j: 9200; D–H: 9100. In panels c, g, h, i and j, reactive T-cells expressing the corresponding T-cell marker are shown by an asterisk.
(Fig. 2) emphasizes that immunohistochemistry was successful and that the null phenotype was not because of technical reasons. © 2014 British Association of Dermatologists
Loss of expression of some immunophenotypic markers in CTCL can be observed2,5,6 especially in advanced T-cell lymphomas, such as Sezary syndrome,1 which was ruled out by British Journal of Dermatology (2015) 172, pp1637–1641
1640 Aberrant immunophenotypes in mycosis fungoides, L. Bekel et al.
Table 1 Previously reported cases of mycosis fungoides with antigen loss/gain of expression
Number of cases
References Tournier et al.
3
Age (years)/ sex (M, F)
1
31/F
Shiomi et al.8
1
20/F
Hodak et al.4
18
11–77/M (n = 13), F (n = 5)
Fierro et al.7
22
22–82/M (n = 14), F (n = 8)
Clinical presentation Infiltrated plaques in photoprotected areas Multiple poikilodermatous patches Classic MF: n = 8; unusual clinical variants: n = 10 (hypopigmented, ichthyosiform, purpuric) Classic plaque presentation (n = 20) Tumour (n = 2)
Stage TNMB (EORTC)
Epidermotropism, Pautrier’s microabscess
CD4+, CD8+ CD5 , CD7
No visceral or lymphadenopathy involvement IA-IB
Epidermotropism Band-like in papillary dermis Superficial dermis perivascular lymphocytic infiltrate with epidermotropism
CD3+, CD4 , CD8+, CD56+, TIA-1+, granzyme B, CD30 CD3+, CD4 , CD8
IA (9), IB (11), IIB (1), IVA (1)
Perivascular, band-like dermal lymphoid infiltrate, moderate to marked epidermotropism Band-like infiltrate, diffuse dermal infiltration, Pautrier’s microabscess
CD45RA+, CD45RO
5
Adults
Plaque/tumour
IC-IIIC
Aung PP et al.10
1
54/F
At diagnosis: multiple scaly and erythematous patches
IIA
Kempf et al.9
1
70/F
Sen et al.11
1
53/F
Histology
IA
Preesman et al.6
At relapse: scaly erythematous plaque with superficial ulceration of the soles Annular erythematous and hypopigmented patches on the left lower leg Erythematous patches and plaques of the right lower extremity, enlarged inguinal lymph node
T-cell antigen loss or aberrant immunophenotype
IA
IVA
At diagnosis: perivascular lymphocytic infiltrate, epidermotropism, folliculotropism At relapse: prominent epidermotropism with pagetoid pattern of growth Epidermis heavily infiltrated by small lymphocytes with chromatin dense nuclei Dense infiltrate of small lymphocytes, with irregular nuclei in the epidermis and superficial dermis with several Pautrier’s microabscesses
CD2 , CD3 , CD4 , CD5 three cases = same aberrant immunophenotype in plaques and tumours two cases = different aberrant immunophenotype in plaques and tumours At diagnosis: CD2 , CD3+, CD4+, CD5 , CD8
At relapse: CD3+, CD4 , CD5 , CD7+, CD8+
CD2+, CD4 , CD8 , CD30 , bF1+, PD1+, CXCL13 , TiA-1, granzyme B, perforine CD2+, CD3+, CD4+, CD5+, CD7 , CD8 , CD20+, TCRc chain gene rearrangement + Immunoglobulin heavy and light chain gene rearrangements not identified
M, male; F, female; EORTC, European Organisation for Research and Treatment of Cancer.
British Journal of Dermatology (2015) 172, pp1637–1641
© 2014 British Association of Dermatologists
Aberrant immunophenotypes in mycosis fungoides, L. Bekel et al. 1641
our observations because of negativity of CD158k/KIR3DL2 staining in the skin. Immunophenotypic aberrations are reported to occur in up to 76.8% of all patients with MF.2,5–7 Besides ‘classical’ aberrations involving loss of one or several pan-T-cell antigens, such as CD2, CD3, CD4, CD5 or CD72,4–6 (most frequently CD2 and CD7,2 followed by CD5 and CD3), cases of MF with coexpression of CD4 and CD8,3 expression of CD8 rather than CD4,8 CD4 CD8 forms (including PD-1 expression)4,9 have been reported (Table 1). In MF, different immunophenotypes in the same patient may occur either simultaneously or during the course of the disease.5,10 Preesman et al.6 reported additional loss of one of the T-cell markers in the tumour rather than in plaques in an individual patient. There are also rare reports of other immunophenotypic aberrations with gain of expression of CD56+,8 CD45RA+7 or CD20+.11 Aberrant expression of TCR molecules with lack of both the ab and cd complex may also be seen, but exclusively in the advanced stages of MF.2,12 MF prognosis is strongly conditioned by the extent/type of skin involvement and the presence of extracutaneous disease. Whether phenotypic aberrations may have an impact on the clinical behaviour and prognosis remains an interesting question. No correlation between aberrant antigenicity and the prognosis has been observed,2,5–7,12 except for higher levels of dermal (but not epidermal) CD30 expression, which were found to be an independent adverse prognostic indicator in MF.13 According to the literature, it is noteworthy that our patients did not seem to have a worse prognosis than patients with classical erythrodermic or plaque stage MF (after follow-up of 6 years in case 1 and 6 months in case 2). On the other hand, in the era of targeted therapies aimed at cell surface markers, patients with antigen loss may not be eligible for new treatments. In our patients, CD30 appeared to be expressed by the majority of the neoplastic T-cells, so that in case of progression towards tumour stage, they may benefit from the new anti-CD30 therapies like brentuximab that are currently under evaluation.14 The association of pyoderma gangrenosum with CTCL, as seen in case 1, is rare and has only been reported twice.15 To conclude, MF with a null T-cell phenotype is unusual. Although in our patients, it did not appear to modify the lymphoma behaviour and evolution, the prognostic impact of T-cell antigen loss in CTCL remains to be studied in a larger series of cases.
© 2014 British Association of Dermatologists
References 1 Willemze R, Jaffe ES, Burg G, et al. WHO–EORTC classification for cutaneous lymphomas. Blood 2005; 105:3768–85. 2 Ralfkiaer E. Controversies and discussion on early diagnosis of cutaneous T-cell lymphoma. Phenotyping. Dermatol Clin 1994; 12:329–34. 3 Tournier E, Laurent C, Thomas M, et al. Double-positive CD4/CD8 mycosis fungoides: a rarely reported immunohistochemical profile. J Cutan Pathol 2014; 41:58–62. 4 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; 55:276–84. 5 van der Putte SC, Toonstra J, van Wichen DF, et al. Aberrant immunophenotypes in mycosis fungoides. Arch Dermatol 1988; 124:373–80. 6 Preesman AH, Toonstra J, van der Putte SC, van Vloten WA. Immunophenotyping on simultaneously occurring plaques and tumours in mycosis fungoides and Sezary syndrome. Br J Dermatol 1993; 129:660–6. 7 Fierro MT, Novelli M, Savoia P, et al. CD45RA+ immunophenotype in mycosis fungoides: clinical, histological and immunophenotypical features in 22 patients. J Cutan Pathol 2001; 28:356–62. 8 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 2013; 40:317–20. 9 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; 34:757–61. 10 Aung PP, Climent F, Muzzafar T, et al. Immunophenotypic shift of CD4 and CD8 antigen expression in primary cutaneous T-cell lymphomas: a clinicopathologic study of three cases. J Cutan Pathol 2014; 41:51–7. 11 Sen F, Kang S, Cangiarella J, et al. CD20 positive mycosis fungoides: a case report. J Cutan Pathol 2008; 35:398–403. 12 Massone C, Crisman G, Kerl H, Cerroni L. The prognosis of early mycosis fungoides is not influenced by phenotype and T-cell clonality. Br J Dermatol 2008; 159:881–6. 13 Edinger JT, Clark BZ, Pucevich BE, et al. CD30 expression and proliferative fraction in nontransformed mycosis fungoides. Am J Surg Pathol 2009; 33:1860–8. 14 Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 2010; 363:1812–21. 15 Ho KK, Browne A, Fitzgibbons J, et al. Mycosis fungoides bullosa simulating pyoderma gangrenosum. Br J Dermatol 2000; 142:124–7.
British Journal of Dermatology (2015) 172, pp1637–1641
British Journal of Dermatology
CASE REPORT
Primary cutaneous T-cell lymphoma presenting as mycosis fungoides with a T-/null-cell phenotype: report of two cases L. Bekel,1 G. Chaby,1 C. Lok,1 A. Dadban,1 D. Chatelain,2 S. Ingen-Housz-Oro3 and N. Ortonne4 1
Department Department 3 Department 4 Department 2
of of of of
Dermatology, H^opital Sud, University of Amiens, 80054 Amiens, France Pathology, H^opital Nord, University of Amiens, 80054 Amiens, France Dermatology, Assistance Publique-H^opitaux de Paris (AP-HP) Groupe Hospitalier Henri Mondor, UPEC University, 94010 Creteil, France Pathology, INSERM U955 Equipe 9, AP-HP, Groupe Hospitalier Henri Mondor, UPEC University, 94010 Creteil, France
Summary Correspondence Lilia Bekel. E-mail: [email protected]
Accepted for publication 9 November 2014
Variations in the clinical and histological presentation of cutaneous T-cell lymphoma (CTCL) can hamper diagnosis. We report two cases of a novel presentation of CTCL characterized by an aberrant immunophenotype with complete loss of pan T-cell antigens including T-cell receptor b chain and showing the clinical and histopathological appearance of erythrodermic and plaque-stage mycosis fungoides.
Funding sources None.
Conflicts of interest None declared. DOI 10.1111/bjd.13563
What’s already known about this topic?
• •
Phenotypic aberrations with loss of some surface antigens are common findings in malignant cutaneous T-cell lymphomas. The almost complete absence of T-cell marker expression in mycosis fungoides has never been reported previously.
What does this study add?
• •
We describe two original observations of cutaneous T-cell lymphoma characterized by an aberrant immunophenotype with loss of pan T-cell antigens including the Tcell receptor b chain. Lymphoma behaviour and evolution does not appear to be modified in these cases.
Cutaneous T-cell lymphoma (CTCL) diagnosis is based on clinical, histological, immunophenotypic and molecular grounds.1,2 The neoplastic cells in mycosis fungoides (MF) usually have a mature CD2+, CD3+, CD4+, CD5+, CD45RO+ and CD8 memory T-cell phenotype.1,2 If phenotypic aberrations with loss of some surface antigens are common findings in CTCL,2–5 the absence of pan-T antigens is rare especially in MF.4,5 We describe two original observations of unusual MF characterized by an aberrant immunophenotype with a complete loss of pan T-cell antigens.
Case report 1
© 2014 British Association of Dermatologists
British Journal of Dermatology (2015) 172, pp1637–1641
A 57-year-old man presented with recurrent episodes of pyoderma gangrenosum of the lower limbs, confirmed by skin biopsies, but the initial staging did not reveal associated underlying disease. Five years later, in December 2007, he presented with an erythroderma with peripheral lymphadenopathy and nodules on the dorsal face of the left foot and the inner side of the right limb (Fig. 1a,b). 1637
1638 Aberrant immunophenotypes in mycosis fungoides, L. Bekel et al.
(a)
(b)
(c)
Fig 1. Clinical presentation. (a) Case 1. Erythroderma of the back. (b) Case 1. Nodular lesion of the right calf. (c) Case 2. Erythematosquamous plaque on the left part of the chest.
The histopathology of both the erythrodermic skin and the nodules revealed similar lesions, with more pronounced features in the nodular lesions. They showed a subepidermal band-like lymphocytic infiltrate with marked epidermotropism associated with diffuse and interstitial infiltration of the dermis. The infiltrate was monomorphic, being composed of slightly atypical lymphocytes with hyperchromatic nuclei, sometimes grouped in clusters and forming Pautrier’s microabscesses within the epidermis (Fig. 2). Immunophenotyping showed that the neoplastic T-cells were negative for all T-cell antigens investigated (CD2, CD3, CD4, CD5, CD7, CD8). Immunostaining for TdT, CD99, CD56, CD25, JUNB and p80/ ALK-1, for cytotoxic markers (granzyme B and TiA1), follicular helper T-cell markers (PD1/CD279, ICOS/CD278 and CD10) and the histiocytic markers CD1a, CD163 were all negative, whereas neoplastic cells strongly expressed CD45 and CD30 (Fig. 2). The Sezary cell marker CD158k (KIR3DL2) was also negative. Interestingly, no T-cell receptor (TCR) b and c chain expression could be demonstrated using immunohistochemistry. Polymerase chain reaction to assess clonality at the TCRc locus demonstrated a dominant T-cell clone in the skin and an oligoclonal pattern in the blood. Full blood cell count was normal with absence of Sezary cells, and the CD4/CD8 ratio was 2.5. Human T-cell lymphotrophic virus and Epstein–Barr virus serological tests were negative. Additionally, a biopsy of a lymphadenopathy was performed and showed only a reactional histological appearance. Thoracic-abdominal-pelvic computed tomography was normal. The diagnosis of stage III MF T4N1M0 [World Health Organization–European Organisation for Research and Treatment of Cancer (WHO–EORTC)] was retained after multidisciplinary consultation and clinicopathological confirmation. The patient responded very well to a combination of daily oral prednisone 10 mg and methotrexate 25 mg weekly. This led to clinical and histological remission. The onset 2 years later of interstitial lung disease required treatment by interferon (3 million units three times per week) and then successive therapeutic changes due to failures: topical carmustine (three British Journal of Dermatology (2015) 172, pp1637–1641
times per week), chlormethine (three times per week) and bexarotene (300 mg m 2). The latter was started 10 months ago with good efficiency to date.
Case report 2 A 71-year-old man presented with erythematous, scaly, noninfiltrated plaques on the limbs and trunk for several months (Fig. 1c). There was no peripheral lymphadenopathy. In May 2013, a skin biopsy showed the appearance of epidermotropic cutaneous T-cell lymphoma. The epidermotropic component consisted of atypical small lymphocytes showing hyperchromatic nuclei aligned along the basement membrane zone (Fig. 2b). Interestingly, using immunohistochemistry, we observed a phenotype similar to that in case 1, with a loss of pan T-cell markers (TCRb and c, CD2, CD3, CD4, CD5, CD7 and CD8). As in case 1, epidermotropic neoplastic cells expressed CD45 and CD30 (Fig. 2) while CD158k/KIR3DL2 was not expressed. All the other markers were negative (TdT, CD99, CD56, CD25, JUNB, p80/ALK-1, granzyme B, TiA1, PD1/CD279, ICOS/CD278, CXCL13 CD10, CD1a and CD163). No TCRc gene rearrangement was detected by polymerase chain reaction in skin or in blood. Blood cell count (including Sezary cells) and computed tomography of the whole body was normal. Stage IA MF T1bN0M0 according to the EORTC–WHO classification was diagnosed. After treatment with topical corticosteroids (clobetasol 0.05%), cutaneous plaques regressed completely.
Discussion The clinical and histological presentation of CTCL is variable so the diagnosis may be challenging and require clinicopathological confirmation. In the cases we observed, clinical and histological features were those of a CTCL. To our knowledge, the almost complete absence of T-cell markers expression in MF has never previously been reported in the literature. The presence of T-reactive cells usually associated with neoplastic T-cells in the MF infiltrates © 2014 British Association of Dermatologists
Aberrant immunophenotypes in mycosis fungoides, L. Bekel et al. 1639
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
(i)
(j)
Fig 2. Histopathology and phenotype: representative pictures of case 1 are presented on the left and pictures of case 2 are shown on the right. (a) Case 1: the lymphoma presented with a band-like subepidermal epidermotropic lymphocytic infiltrate made of atypical small lymphocytes with hyperchromatic nuclei, often grouped in clusters (Pautrier’s microabscesses) in the epidermis. (b) Case 2: the epidermotropic component was more subtle, made of small atypical lymphocytes with hyperchromatic nuclei aligned along the basement membrane. (c) TCRb negativity in case 1. (d) All neoplastic cells expressed CD30 in case 1. (e, f) CD45 and CD30 positivity in case 2. (g, h) Negativity CD4 and CD8 staining in case 1. (i, j) Negative staining for CD3 and CD5 in case 2. Arrows show epidermotropic lymphocytes grouped in Pautrier’s microabscesses, and arrowheads show neoplastic lymphocytes aligned along the basement membrane. (a, b) Haematoxylin and eosin stain; (c–j) immunostaining revealed by diaminobenzidine. Original magnifications: a, b, c, i, j: 9200; D–H: 9100. In panels c, g, h, i and j, reactive T-cells expressing the corresponding T-cell marker are shown by an asterisk.
(Fig. 2) emphasizes that immunohistochemistry was successful and that the null phenotype was not because of technical reasons. © 2014 British Association of Dermatologists
Loss of expression of some immunophenotypic markers in CTCL can be observed2,5,6 especially in advanced T-cell lymphomas, such as Sezary syndrome,1 which was ruled out by British Journal of Dermatology (2015) 172, pp1637–1641
1640 Aberrant immunophenotypes in mycosis fungoides, L. Bekel et al.
Table 1 Previously reported cases of mycosis fungoides with antigen loss/gain of expression
Number of cases
References Tournier et al.
3
Age (years)/ sex (M, F)
1
31/F
Shiomi et al.8
1
20/F
Hodak et al.4
18
11–77/M (n = 13), F (n = 5)
Fierro et al.7
22
22–82/M (n = 14), F (n = 8)
Clinical presentation Infiltrated plaques in photoprotected areas Multiple poikilodermatous patches Classic MF: n = 8; unusual clinical variants: n = 10 (hypopigmented, ichthyosiform, purpuric) Classic plaque presentation (n = 20) Tumour (n = 2)
Stage TNMB (EORTC)
Epidermotropism, Pautrier’s microabscess
CD4+, CD8+ CD5 , CD7
No visceral or lymphadenopathy involvement IA-IB
Epidermotropism Band-like in papillary dermis Superficial dermis perivascular lymphocytic infiltrate with epidermotropism
CD3+, CD4 , CD8+, CD56+, TIA-1+, granzyme B, CD30 CD3+, CD4 , CD8
IA (9), IB (11), IIB (1), IVA (1)
Perivascular, band-like dermal lymphoid infiltrate, moderate to marked epidermotropism Band-like infiltrate, diffuse dermal infiltration, Pautrier’s microabscess
CD45RA+, CD45RO
5
Adults
Plaque/tumour
IC-IIIC
Aung PP et al.10
1
54/F
At diagnosis: multiple scaly and erythematous patches
IIA
Kempf et al.9
1
70/F
Sen et al.11
1
53/F
Histology
IA
Preesman et al.6
At relapse: scaly erythematous plaque with superficial ulceration of the soles Annular erythematous and hypopigmented patches on the left lower leg Erythematous patches and plaques of the right lower extremity, enlarged inguinal lymph node
T-cell antigen loss or aberrant immunophenotype
IA
IVA
At diagnosis: perivascular lymphocytic infiltrate, epidermotropism, folliculotropism At relapse: prominent epidermotropism with pagetoid pattern of growth Epidermis heavily infiltrated by small lymphocytes with chromatin dense nuclei Dense infiltrate of small lymphocytes, with irregular nuclei in the epidermis and superficial dermis with several Pautrier’s microabscesses
CD2 , CD3 , CD4 , CD5 three cases = same aberrant immunophenotype in plaques and tumours two cases = different aberrant immunophenotype in plaques and tumours At diagnosis: CD2 , CD3+, CD4+, CD5 , CD8
At relapse: CD3+, CD4 , CD5 , CD7+, CD8+
CD2+, CD4 , CD8 , CD30 , bF1+, PD1+, CXCL13 , TiA-1, granzyme B, perforine CD2+, CD3+, CD4+, CD5+, CD7 , CD8 , CD20+, TCRc chain gene rearrangement + Immunoglobulin heavy and light chain gene rearrangements not identified
M, male; F, female; EORTC, European Organisation for Research and Treatment of Cancer.
British Journal of Dermatology (2015) 172, pp1637–1641
© 2014 British Association of Dermatologists
Aberrant immunophenotypes in mycosis fungoides, L. Bekel et al. 1641
our observations because of negativity of CD158k/KIR3DL2 staining in the skin. Immunophenotypic aberrations are reported to occur in up to 76.8% of all patients with MF.2,5–7 Besides ‘classical’ aberrations involving loss of one or several pan-T-cell antigens, such as CD2, CD3, CD4, CD5 or CD72,4–6 (most frequently CD2 and CD7,2 followed by CD5 and CD3), cases of MF with coexpression of CD4 and CD8,3 expression of CD8 rather than CD4,8 CD4 CD8 forms (including PD-1 expression)4,9 have been reported (Table 1). In MF, different immunophenotypes in the same patient may occur either simultaneously or during the course of the disease.5,10 Preesman et al.6 reported additional loss of one of the T-cell markers in the tumour rather than in plaques in an individual patient. There are also rare reports of other immunophenotypic aberrations with gain of expression of CD56+,8 CD45RA+7 or CD20+.11 Aberrant expression of TCR molecules with lack of both the ab and cd complex may also be seen, but exclusively in the advanced stages of MF.2,12 MF prognosis is strongly conditioned by the extent/type of skin involvement and the presence of extracutaneous disease. Whether phenotypic aberrations may have an impact on the clinical behaviour and prognosis remains an interesting question. No correlation between aberrant antigenicity and the prognosis has been observed,2,5–7,12 except for higher levels of dermal (but not epidermal) CD30 expression, which were found to be an independent adverse prognostic indicator in MF.13 According to the literature, it is noteworthy that our patients did not seem to have a worse prognosis than patients with classical erythrodermic or plaque stage MF (after follow-up of 6 years in case 1 and 6 months in case 2). On the other hand, in the era of targeted therapies aimed at cell surface markers, patients with antigen loss may not be eligible for new treatments. In our patients, CD30 appeared to be expressed by the majority of the neoplastic T-cells, so that in case of progression towards tumour stage, they may benefit from the new anti-CD30 therapies like brentuximab that are currently under evaluation.14 The association of pyoderma gangrenosum with CTCL, as seen in case 1, is rare and has only been reported twice.15 To conclude, MF with a null T-cell phenotype is unusual. Although in our patients, it did not appear to modify the lymphoma behaviour and evolution, the prognostic impact of T-cell antigen loss in CTCL remains to be studied in a larger series of cases.
© 2014 British Association of Dermatologists
References 1 Willemze R, Jaffe ES, Burg G, et al. WHO–EORTC classification for cutaneous lymphomas. Blood 2005; 105:3768–85. 2 Ralfkiaer E. Controversies and discussion on early diagnosis of cutaneous T-cell lymphoma. Phenotyping. Dermatol Clin 1994; 12:329–34. 3 Tournier E, Laurent C, Thomas M, et al. Double-positive CD4/CD8 mycosis fungoides: a rarely reported immunohistochemical profile. J Cutan Pathol 2014; 41:58–62. 4 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; 55:276–84. 5 van der Putte SC, Toonstra J, van Wichen DF, et al. Aberrant immunophenotypes in mycosis fungoides. Arch Dermatol 1988; 124:373–80. 6 Preesman AH, Toonstra J, van der Putte SC, van Vloten WA. Immunophenotyping on simultaneously occurring plaques and tumours in mycosis fungoides and Sezary syndrome. Br J Dermatol 1993; 129:660–6. 7 Fierro MT, Novelli M, Savoia P, et al. CD45RA+ immunophenotype in mycosis fungoides: clinical, histological and immunophenotypical features in 22 patients. J Cutan Pathol 2001; 28:356–62. 8 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 2013; 40:317–20. 9 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; 34:757–61. 10 Aung PP, Climent F, Muzzafar T, et al. Immunophenotypic shift of CD4 and CD8 antigen expression in primary cutaneous T-cell lymphomas: a clinicopathologic study of three cases. J Cutan Pathol 2014; 41:51–7. 11 Sen F, Kang S, Cangiarella J, et al. CD20 positive mycosis fungoides: a case report. J Cutan Pathol 2008; 35:398–403. 12 Massone C, Crisman G, Kerl H, Cerroni L. The prognosis of early mycosis fungoides is not influenced by phenotype and T-cell clonality. Br J Dermatol 2008; 159:881–6. 13 Edinger JT, Clark BZ, Pucevich BE, et al. CD30 expression and proliferative fraction in nontransformed mycosis fungoides. Am J Surg Pathol 2009; 33:1860–8. 14 Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 2010; 363:1812–21. 15 Ho KK, Browne A, Fitzgibbons J, et al. Mycosis fungoides bullosa simulating pyoderma gangrenosum. Br J Dermatol 2000; 142:124–7.
British Journal of Dermatology (2015) 172, pp1637–1641
