Case report
zary syndrome with concomitant pulmonary An unusual Se localization: aggressiveness of folliculotropic form Charlotte Brugiere1,2, MD, Andrea Stefan1,2, MD, Veronique Salaun3, MD, Francßois Comoz4, MD, Karine Campbell5, MD, Sylvain Chantepie3, MD, and Laurence Verneuil1,2, MD, PHD
1 Department of Dermatology, CHU de Caen, Caen, France, 2Medical School, de Caen Basse-Nomandie, Universite Caen, France, 3Department of Haematology, CHU de Caen, Caen, France, 4Department of Pathology, CHU de Caen, Caen, France, and 5Department of Pulmonary, CHU de Caen, Caen, France
Correspondence Laurence Verneuil, MD, PHD Dermatology Department, CHU Caen, Avenue Georges Clemenceau, F-14033 Caen, France E-mail: [email protected] Conflicts of interest: None.
Introduction
Case report
Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas arising from T cells that home to and persist in the skin.1,2 Mycosis fungoides (MF) and Sezary syndrome account for approximately 65% of CTCL.3 They were considered as different stages in the same disease, but recent genetic and phenotypic studies suggest that they arise from two distinct T-cell subsets.4,5 Folliculotropic MF, a follicular variant of classic MF, is discussed separately because of its distinct clinicopathological features3 and a more aggressive clinical course, with poorer prognosis than in classic MF.6 It is characterized by folliculotropic infiltrates, often sparing the epidermis, and clinically by follicular papules, comedones, cysts of preferentially head and neck areas, or by alopecia. It is frequently refractory to usual therapies.6 Sezary syndrome is an aggressive clinical entity associated with poor prognosis and a median survival of 2–3 years. Folliculotropic Sezary syndrome, a clinical variant, is exceptional, and we report a case of folliculotropic Sezary syndrome with a concomitant pulmonary localization.
We report a 64-year-old man with a 1-month history of pruritic erythroderma, which covered more than 80% of the body surface area and was associated with infiltrated leonine facies, follicular papules of the head and neck, alopecia of the scalp (Fig. 1a), and palmoplantar keratoderma. Cervical, axillary, and inguinal lymphadenopathy were detected. Skin biopsy showed no epidermotropism but follicular mucinosis was confirmed by alcian blue staining (Fig. 1b) and lymphocyte aggregates composed of small- to intermediate-sized lymphocytes with irregular nuclei (Fig. 1c) expressing CD3/CD4/CD5 with a loss of CD7 and CD8 around the hair follicles. An abnormal cutaneous T-cell population expressing CD2/CD3/CD4/CD5 with a loss of CD7 and CD26 expression was evidenced using flow cytometric immunophenotyping. Inguinal lymphadenectomy showed localization of a malignant lymphoproliferative T-cell population. In the blood and inguinal lymphadenectomy, using flow-cytometric immunophenotyping, the same T-cell population was detected. The white blood cell count showed 6.0 9 109/l lymphocytes with 1200/mm3 Sezary
ª 2014 The International Society of Dermatology
International Journal of Dermatology 2016, 55, 81–84
81
82
Case report
Brugie re et al.
An unusual folliculotropic Se´zary syndrome
(a)
(b)
(c)
Figure 1 Clinical and histological data of our patient. (a) Infiltrated leonine facies with alopecia of the scalp and follicular papules of the head. (b) Follicular mucinosis and aggregates of lymphocytes around hair follicles; alcian blue staining, 9 200. (c) Smallto intermediate-sized lymphocytes with irregular nuclei at the lower part of the hair follicle bulb; hematoxylin– eosin–safran staining, 9 400
cells and a CD4/CD8 ratio at 41. HTLV-1 detection was negative. A computed tomography scan showed bilateral reticular infiltrates, and bronchoalveolar fluid analyses, using flow-cytometric immunophenotyping, detected the same abnormal T-cell population CD2+/CD3+/CD4+/CD5+/ CD7 /CD8 /CD26 as in the skin, blood, and lymph node. No red blood cell was detected in the bronchoalveolar fluid, excluding blood contamination. The same T-cell clone was detected in the skin, blood, lymph nodes, and bronchoalveolar fluid. These data were characteristic of a folliculotropic Sezary syndrome with a concomitant pulmonary localization, corresponding to a T4N2M1B2 stage, clinical stage IVB. There was no other extracutaneous infiltration. Despite intensive treatment with cyclophosphamide/ doxorubicin/vincristine/prednisone started immediately in our patient, he died five months after the diagnosis due to an acute respiratory distress syndrome probably secondary to the progression of pulmonary lymphoma. International Journal of Dermatology 2016, 55, 81–84
Discussion Sezary syndrome characterized by a folliculotropism (folliculotropic Sezary syndrome) is exceptional with only eight cases previously reported7–13 (Table 1). In our patient, aggressiveness was remarkable with concomitant pulmonary lymphoma localization at the onset of disease. Currently, as in our case, a quick extracutaneous involvement has been described in four of nine patients (44%) with folliculotropic Sezary syndrome, showing a strong aggressiveness when a folliculotropism is present7,8,13 (Table 1). This fact suggests that factors other than therapeutic resistance alone, which was recorded in folliculotropic MF,14,15 could be involved in this agressiveness. The T lymphocytes found in the folliculotropic form of CTCL could be characterized by greater visceral tropism. This raises the question of the molecular and functional characteristics of these T lymphocytes and the possibility of a common target in hair follicles and certain organs. Studies have shown that chemokine receptors are likely to be involved in the skin tropism that characterizes CTCL.16,17 Molecular study characterizing ª 2014 The International Society of Dermatology
Brugie re et al.
5 months At the diagnosis Yes
Lung
At the diagnosis Bone marrow
ND ND, in life after 5 years ND, in life after 2 years In life
M
< 1 year
5 months Bone marrow
Yes Yes Yes Yes
Follicular dermatosis, nodules, alopecia Erythroderma, follicular papules, leonine facies Erythroderma, follicular papules, alopecia Erythroderma, follicular papules, leonine facies, keratoderma Erythroderma, follicular papules, leonine facies, keratoderma, alopecia F M M M
2 years ND ND 5 months
Our case, 2012
Jang13
Mehta7 Gerami12
zary syndrome Se zary syndrome Se zary syndrome Se Cutaneous CD30+ folliculotropic zary lymphoma with circulating Se cells zary syndrome Se zary syndrome Se zary syndrome Se zary syndrome with CD25+ Se CD30+ large cell transformation zary syndrome Se Westfried9 Rivers10 LeBoit11 Tremeau-Martinage8
M M F M
Follicular papules, keratoderma Erythroderma, nodules, small milia, alopecia Erythema, follicular papules, alopecia Follicular papules
Yes No Yes Yes
Bone marrow
Survival Sex Type of folliculotropic lymphoma
ª 2014 The International Society of Dermatology
Case report
and comparing T lymphocytes of folliculotropic CTCL and T lymphocytes of non-folliculotropic CTCL could be investigated.
Cases reported
Table 1 Reported cases of folliculotropic S ezary syndrome
Cutaneous data
Adenopathy
Extracutaneous involvement
Time to visceral involvement
An unusual folliculotropic Se´zary syndrome
Acknowledgements We wish to thank A. Swaine, who reviewed the English language. References 1 Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007; 110: 1713–1722. 2 Girardi M, Heald PW, Wilson LD. The pathogenesis of mycosis fungoides. N Engl J Med 2004; 350: 1978–1988. 3 Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768–3785. 4 Campbell JJ, Clark RA, Watanabe R, et al. Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. Blood 2010; 116: 767–771. 5 van Doorn R, van Kester MS, Dijkman R, et al. Oncogenomic analysis of mycosis fungoides reveals major differences with Sezary syndrome. Blood 2009; 113: 127– 136. 6 van Doorn R, Scheffer E, Willemze R. Follicular mycosis fungoides, a distinct disease entity with or without associated follicular mucinosis: a clinicopathologic and follow-up study of 51 patients. Arch Dermatol 2002; 138: 191–198. 7 Mehta A, Dhungel BM, Khan MF. Mycosis fungoides/ Sezary syndrome: report of an unusual case. J Cutan Pathol 2006; 33(Suppl. 2): 12–15. 8 Tremeau-Martinage C, Gorguet B, Lamant L, et al. [CD30 positive pilotropic lymphoma]. Ann Dermatol Venereol 1999; 126: 434–438. 9 Westfried M, Rosenthal JC, Coppola A, et al. Sezary syndrome presenting as a follicular dermatosis. Cutis 1982; 29: 394–396. 10 Rivers JK, Norris PG, Greaves MW, et al. Follicular mucinosis in association with Sezary syndrome. Clin Exp Dermatol 1987; 12: 207–210. 11 LeBoit PE, Abel EA, Cleary ML, et al. Clonal rearrangement of the T cell receptor beta gene in the circulating lymphocytes of erythrodermic follicular mucinosis. Blood 1988; 71: 1329–1333. 12 Gerami P, Guitart J. Folliculotropic Sezary syndrome: a new variant of cutaneous T-cell lymphoma. Br J Dermatol 2007; 156: 781–783.
International Journal of Dermatology 2016, 55, 81–84
83
84
Case report
An unusual folliculotropic Se´zary syndrome
13 Jang MS, Kang DY, Han SH, et al. CD25+ folliculotropic Sezary syndrome with CD30+ large cell transformation. Australas J Dermatol 2012; doi: 10.1111/ajd.12000. [Epub ahead of print]. 14 Benner MF, Jansen PM, Vermeer MH, et al. Prognostic factors in transformed mycosis fungoides: a retrospective analysis of 100 cases. Blood 2012; 119: 1643–1649. 15 Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/ Sezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European
International Journal of Dermatology 2016, 55, 81–84
Brugie re et al.
Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 2010; 28: 4730–4739. 16 Wu XS, Lonsdorf AS, Hwang ST. Cutaneous T-cell lymphoma: roles for chemokines and chemokine receptors. J Invest Dermatol 2009; 129: 1115–1119. 17 Yagi H, Seo N, Ohshima A, et al. Chemokine receptor expression in cutaneous T cell and NK/T-cell lymphomas: immunohistochemical staining and in vitro chemotactic assay. Am J Surg Pathol 2006; 30: 1111–1119.
ª 2014 The International Society of Dermatology
zary syndrome with concomitant pulmonary An unusual Se localization: aggressiveness of folliculotropic form Charlotte Brugiere1,2, MD, Andrea Stefan1,2, MD, Veronique Salaun3, MD, Francßois Comoz4, MD, Karine Campbell5, MD, Sylvain Chantepie3, MD, and Laurence Verneuil1,2, MD, PHD
1 Department of Dermatology, CHU de Caen, Caen, France, 2Medical School, de Caen Basse-Nomandie, Universite Caen, France, 3Department of Haematology, CHU de Caen, Caen, France, 4Department of Pathology, CHU de Caen, Caen, France, and 5Department of Pulmonary, CHU de Caen, Caen, France
Correspondence Laurence Verneuil, MD, PHD Dermatology Department, CHU Caen, Avenue Georges Clemenceau, F-14033 Caen, France E-mail: [email protected] Conflicts of interest: None.
Introduction
Case report
Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of non-Hodgkin lymphomas arising from T cells that home to and persist in the skin.1,2 Mycosis fungoides (MF) and Sezary syndrome account for approximately 65% of CTCL.3 They were considered as different stages in the same disease, but recent genetic and phenotypic studies suggest that they arise from two distinct T-cell subsets.4,5 Folliculotropic MF, a follicular variant of classic MF, is discussed separately because of its distinct clinicopathological features3 and a more aggressive clinical course, with poorer prognosis than in classic MF.6 It is characterized by folliculotropic infiltrates, often sparing the epidermis, and clinically by follicular papules, comedones, cysts of preferentially head and neck areas, or by alopecia. It is frequently refractory to usual therapies.6 Sezary syndrome is an aggressive clinical entity associated with poor prognosis and a median survival of 2–3 years. Folliculotropic Sezary syndrome, a clinical variant, is exceptional, and we report a case of folliculotropic Sezary syndrome with a concomitant pulmonary localization.
We report a 64-year-old man with a 1-month history of pruritic erythroderma, which covered more than 80% of the body surface area and was associated with infiltrated leonine facies, follicular papules of the head and neck, alopecia of the scalp (Fig. 1a), and palmoplantar keratoderma. Cervical, axillary, and inguinal lymphadenopathy were detected. Skin biopsy showed no epidermotropism but follicular mucinosis was confirmed by alcian blue staining (Fig. 1b) and lymphocyte aggregates composed of small- to intermediate-sized lymphocytes with irregular nuclei (Fig. 1c) expressing CD3/CD4/CD5 with a loss of CD7 and CD8 around the hair follicles. An abnormal cutaneous T-cell population expressing CD2/CD3/CD4/CD5 with a loss of CD7 and CD26 expression was evidenced using flow cytometric immunophenotyping. Inguinal lymphadenectomy showed localization of a malignant lymphoproliferative T-cell population. In the blood and inguinal lymphadenectomy, using flow-cytometric immunophenotyping, the same T-cell population was detected. The white blood cell count showed 6.0 9 109/l lymphocytes with 1200/mm3 Sezary
ª 2014 The International Society of Dermatology
International Journal of Dermatology 2016, 55, 81–84
81
82
Case report
Brugie re et al.
An unusual folliculotropic Se´zary syndrome
(a)
(b)
(c)
Figure 1 Clinical and histological data of our patient. (a) Infiltrated leonine facies with alopecia of the scalp and follicular papules of the head. (b) Follicular mucinosis and aggregates of lymphocytes around hair follicles; alcian blue staining, 9 200. (c) Smallto intermediate-sized lymphocytes with irregular nuclei at the lower part of the hair follicle bulb; hematoxylin– eosin–safran staining, 9 400
cells and a CD4/CD8 ratio at 41. HTLV-1 detection was negative. A computed tomography scan showed bilateral reticular infiltrates, and bronchoalveolar fluid analyses, using flow-cytometric immunophenotyping, detected the same abnormal T-cell population CD2+/CD3+/CD4+/CD5+/ CD7 /CD8 /CD26 as in the skin, blood, and lymph node. No red blood cell was detected in the bronchoalveolar fluid, excluding blood contamination. The same T-cell clone was detected in the skin, blood, lymph nodes, and bronchoalveolar fluid. These data were characteristic of a folliculotropic Sezary syndrome with a concomitant pulmonary localization, corresponding to a T4N2M1B2 stage, clinical stage IVB. There was no other extracutaneous infiltration. Despite intensive treatment with cyclophosphamide/ doxorubicin/vincristine/prednisone started immediately in our patient, he died five months after the diagnosis due to an acute respiratory distress syndrome probably secondary to the progression of pulmonary lymphoma. International Journal of Dermatology 2016, 55, 81–84
Discussion Sezary syndrome characterized by a folliculotropism (folliculotropic Sezary syndrome) is exceptional with only eight cases previously reported7–13 (Table 1). In our patient, aggressiveness was remarkable with concomitant pulmonary lymphoma localization at the onset of disease. Currently, as in our case, a quick extracutaneous involvement has been described in four of nine patients (44%) with folliculotropic Sezary syndrome, showing a strong aggressiveness when a folliculotropism is present7,8,13 (Table 1). This fact suggests that factors other than therapeutic resistance alone, which was recorded in folliculotropic MF,14,15 could be involved in this agressiveness. The T lymphocytes found in the folliculotropic form of CTCL could be characterized by greater visceral tropism. This raises the question of the molecular and functional characteristics of these T lymphocytes and the possibility of a common target in hair follicles and certain organs. Studies have shown that chemokine receptors are likely to be involved in the skin tropism that characterizes CTCL.16,17 Molecular study characterizing ª 2014 The International Society of Dermatology
Brugie re et al.
5 months At the diagnosis Yes
Lung
At the diagnosis Bone marrow
ND ND, in life after 5 years ND, in life after 2 years In life
M
< 1 year
5 months Bone marrow
Yes Yes Yes Yes
Follicular dermatosis, nodules, alopecia Erythroderma, follicular papules, leonine facies Erythroderma, follicular papules, alopecia Erythroderma, follicular papules, leonine facies, keratoderma Erythroderma, follicular papules, leonine facies, keratoderma, alopecia F M M M
2 years ND ND 5 months
Our case, 2012
Jang13
Mehta7 Gerami12
zary syndrome Se zary syndrome Se zary syndrome Se Cutaneous CD30+ folliculotropic zary lymphoma with circulating Se cells zary syndrome Se zary syndrome Se zary syndrome Se zary syndrome with CD25+ Se CD30+ large cell transformation zary syndrome Se Westfried9 Rivers10 LeBoit11 Tremeau-Martinage8
M M F M
Follicular papules, keratoderma Erythroderma, nodules, small milia, alopecia Erythema, follicular papules, alopecia Follicular papules
Yes No Yes Yes
Bone marrow
Survival Sex Type of folliculotropic lymphoma
ª 2014 The International Society of Dermatology
Case report
and comparing T lymphocytes of folliculotropic CTCL and T lymphocytes of non-folliculotropic CTCL could be investigated.
Cases reported
Table 1 Reported cases of folliculotropic S ezary syndrome
Cutaneous data
Adenopathy
Extracutaneous involvement
Time to visceral involvement
An unusual folliculotropic Se´zary syndrome
Acknowledgements We wish to thank A. Swaine, who reviewed the English language. References 1 Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007; 110: 1713–1722. 2 Girardi M, Heald PW, Wilson LD. The pathogenesis of mycosis fungoides. N Engl J Med 2004; 350: 1978–1988. 3 Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768–3785. 4 Campbell JJ, Clark RA, Watanabe R, et al. Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical behaviors. Blood 2010; 116: 767–771. 5 van Doorn R, van Kester MS, Dijkman R, et al. Oncogenomic analysis of mycosis fungoides reveals major differences with Sezary syndrome. Blood 2009; 113: 127– 136. 6 van Doorn R, Scheffer E, Willemze R. Follicular mycosis fungoides, a distinct disease entity with or without associated follicular mucinosis: a clinicopathologic and follow-up study of 51 patients. Arch Dermatol 2002; 138: 191–198. 7 Mehta A, Dhungel BM, Khan MF. Mycosis fungoides/ Sezary syndrome: report of an unusual case. J Cutan Pathol 2006; 33(Suppl. 2): 12–15. 8 Tremeau-Martinage C, Gorguet B, Lamant L, et al. [CD30 positive pilotropic lymphoma]. Ann Dermatol Venereol 1999; 126: 434–438. 9 Westfried M, Rosenthal JC, Coppola A, et al. Sezary syndrome presenting as a follicular dermatosis. Cutis 1982; 29: 394–396. 10 Rivers JK, Norris PG, Greaves MW, et al. Follicular mucinosis in association with Sezary syndrome. Clin Exp Dermatol 1987; 12: 207–210. 11 LeBoit PE, Abel EA, Cleary ML, et al. Clonal rearrangement of the T cell receptor beta gene in the circulating lymphocytes of erythrodermic follicular mucinosis. Blood 1988; 71: 1329–1333. 12 Gerami P, Guitart J. Folliculotropic Sezary syndrome: a new variant of cutaneous T-cell lymphoma. Br J Dermatol 2007; 156: 781–783.
International Journal of Dermatology 2016, 55, 81–84
83
84
Case report
An unusual folliculotropic Se´zary syndrome
13 Jang MS, Kang DY, Han SH, et al. CD25+ folliculotropic Sezary syndrome with CD30+ large cell transformation. Australas J Dermatol 2012; doi: 10.1111/ajd.12000. [Epub ahead of print]. 14 Benner MF, Jansen PM, Vermeer MH, et al. Prognostic factors in transformed mycosis fungoides: a retrospective analysis of 100 cases. Blood 2012; 119: 1643–1649. 15 Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/ Sezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European
International Journal of Dermatology 2016, 55, 81–84
Brugie re et al.
Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol 2010; 28: 4730–4739. 16 Wu XS, Lonsdorf AS, Hwang ST. Cutaneous T-cell lymphoma: roles for chemokines and chemokine receptors. J Invest Dermatol 2009; 129: 1115–1119. 17 Yagi H, Seo N, Ohshima A, et al. Chemokine receptor expression in cutaneous T cell and NK/T-cell lymphomas: immunohistochemical staining and in vitro chemotactic assay. Am J Surg Pathol 2006; 30: 1111–1119.
ª 2014 The International Society of Dermatology
