Mycosis Fungoides, then and now Have we travelled?

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1 USCAP 103 rd Annual Meeting 2014 American Society of Dermatopathology Companion Meeting Mycosis Fungoides, then and now Have we travelled? Vijaya B. Reddy, MD, MBA Professor of Pathology Rush University Medical Center Chicago, IL

2 Mycosis Fungoides Alibert in 1806 Patient whose skin lesions developed into mushroom like tumors Invariably fatal Bazin in 1862 Three classical stages: patch, plaque and tumor Brocq in 1902 Parapsoriasis (large and small plaque) Sézary syndrome 1938 Variants: Pagetoid reticulosis (1939) Folliculotropic (1957) Granulomatous MF (1970) Hypopigmented MF Pustular MF

3 Cutaneous T Cell Lymphoma 1975 Cutaneous T cell lymphomas: the Sézary syndrome, mycosis fungoides, and related disorders. Lutzner M, Edelson R, Schein P, Green I, Kirkpatrick C, Ahmed A. Ann Intern Med Oct;83(4): Substantial evidence has accumulated to indicate not only that mycosis fungoides and the Sézary syndrome are closely related malignancies, but to suggest that they are part of a larger spectrum of cutaneous lymphomas. The neoplastic cells of these disorders have membrane features of thymus derived (T) lymphocytes, a characteristic tissue distribution (skin infiltration, marrow sparing, localization in T cell regions of lymphoid tissue), and distinctive morphology. For these reasons, we suggest that these lymphoproliferative disorders be grouped together as "cutaneous T cell lymphomas".

4 Historic overview on different concepts on the classification of cutaneous lymphomas EORTC Classification for Primary Cutaneous Lymphomas: The Best Guide to Good Clinical Management. Willemze, Rein; Meijer, Chris American Journal of Dermatopathology. 21(3): , June Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

5 EORTC classification for Primary Cutaneous Lymphomas (1997) EORTC Classification for Primary Cutaneous Lymphomas: The Best Guide to Good Clinical Management. Willemze, Rein; Meijer, Chris American Journal of Dermatopathology. 21(3): , June Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

6 Classification of disease entities of the EORTC in the proposed WHO classification EORTC Classification for Primary Cutaneous Lymphomas: The Best Guide to Good Clinical Management. Willemze, Rein; Meijer, Chris American Journal of Dermatopathology. 21(3): , June Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2

7 WHO EORTC and WHO 2008 Classification Cutaneous T Cell Lymphomas 78% Cutaneous B Cell Lymphomas 22% Mycosis fungoides Variants of MF Folliculotropic Granulomatous slack skin Pagetoid reticulosis Sezary syndrome CD30+ Lymphoproliferative disorders Cutaneous anaplastic large cell lymphoma (C ALCL) Lymphomatoid papulosis (LyP) Subcutaneous panniculitis like T Cell lymphoma ExtranodalNK/T cell lymphoma Primary cutaneous PTCL, NOS and variants Primary cutaneous marginal zone B cell lymphoma Primary cutaneous follicle center lymphoma Primary cutaneous diffuse large B cell lymphoma, leg type Intravascular B cell lymphoma Willemze R, Jaffe ES, Burg G et al. WHO EORTC classification for cutaneous lymphomas. Blood. 2005; 105 (10):

8 CTCL: Relative Frequency and Disease Specific Survival EORTC WHO Classification Frequency % 5 year survival % Indolent Mycosis fungoides Follicular mycosis fungoides Pagetoid reticulosis Granulomatous slack skin CD30 + lymphoproliferative diseases Anaplastic large cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis like T cell lymphoma CD4 + small/medium pleomorphic T cell lymphoma 44 4 <1 < Aggressive Sézary syndrome Cutaneous peripheral T cell lymphoma, unspecified Cutaneous aggressive CD8 + T cell lymphoma Cutaneous γ/δ T cell lymphoma Cutaneous NK/T cell lymphoma, nasal type 3 2 <1 <1 < Willemze R, Jaffe ES, Burg G et al. WHO EORTC classification for cutaneous lymphomas. Blood. 2005; 105 (10):

9 Mycosis Fungoides Most common type of CTCL Mostly adults (55 60 years of age) with male predominance ( :1) May affect children/adolescents Epidermotropic proliferation of small to medium sized T helper (CD4+) cells with cerebriform nuclei Indolent course spanning from years to decades with slow progression patch plaque tumors Systemic disease develops in minority of patients

10 Mycosis Fungoides Initial skin lesions tend to occur on the buttocks and other sun protected areas Patients in advanced stages show a combination of patches, plaques, and tumors Ulceration can occur Histopathology: Epidermotropism with Pautrier microabscesses, atypical lymphocytes with haloed appearance, minimal to absent spongiosis Phenotype: Most are CD4+ memory T cells, ~15% CD8+; loss of pan T cell markers (CD2, 3, 4, 5) not uncommon

11 CD3 CD5 CD4 CD8

12 Mycosis Fungoides: Diagnosis Dependent on a combination of clinical and histopathologic criteria which may be supplemented with Immunohistochemistry Molecular (gene rearrangement) studies

13 Mycosis Fungoides: Some Controversies and Advances Parapsoriasis en plaques, digitate dermatosis and patch stage MF Granulomatous slack skin and granulomatous MF Alopecial mucinosa and folliculotropic MF Transformed MF and CD30+ALCL Sezary syndrome and erythrodermic MF

14 Parapsoriasis of Brocq Large plaque parapsoriasis Parapsoriasis en plaques Parapsoriasis Lichenoides Parapsoriasis Variegata Xanthoerythroderma perstans Poikiloderma vasculare atrophicans Small plaque parapsoriasis Digitate dermatosis Parapsoriasis guttata Both convert or transform rarely to mycosis fungoides

15 Large plaque parapsoriasis is mycosis fungoides!! that specific histologic diagnosis of mycosis fungoides cannot be made in the premycotic" or "eczematous" (patch) stage of the disease. that histologic features of the premycotic lesions were constantly said to be those of "chronic non specific dermatitis. 46 biopsy specimens of patch lesions from patients in whom mycosis fungoides was unequivocally established by clinical events (i.e., concurrence or later development of typical plaque and/or nodular lesions) and indubitable histologic findings Histologic diagnosis can be made with near certainty in patch lesions of the disease. increased number of mononuclear cells distributed singly or in small collections within an epidermis devoid of spongiotic microvesiculation. lacunae surrounding intraepidermal mononuclear cells which gives them the appearance of "haloed cells. Atypical mononuclear cells are not necessary for the diagnosis of early patch lesions of mycosis fungoides but are found in late patch lesions Sanchez JL, Ackerman AB. The patch stage of mycosis fungoides. Criteria for histologic diagnosis. Am J Dermatopathol Spring;1(1):5 26.

16 Guttate parapsoriasis/digitate dermatosis (small plaque parapsoriasis) is mycosis fungoides..authors of most textbooks of dermatology and dermatopathology consider guttate parapsoriasis and digitate dermatosis to be variants of small plaque parapsoriasis which, they aver, is not related to mycosis fungoides. On the basis of a study of clinical and histopathologic findings in guttate parapsoriasis and digitate dermatosis, we conclude that those conditions actually represent two of the many clinical faces of mycosis fungoides. King Ismael D, Ackerman AB. Am J Dermatopathol Dec;14(6):518 30; discussion

17 Algorithm for the diagnosis of early MF+ Criteria Clinical Persistent and/or progressive patches and plaques plus (1) Non sun exposed location (2) Size/shape variation (3) Poikiloderma Histopathologic Superficial lymphoid infiltrate plus (1) Epidermotropism without spongiosis (2) Lymphoid atypia* Major (2 points) Any 2 Both Minor (1 point) Any1 Either Molecular/biologic: clonal TCR gene rearrangemen NA Present Immunopathologic (1) CD2, 3, 5, less than 50% of T cells (2) CD7 less than 10% of T cells (3) Epidermal discordance from expression of CD2, 3, 5 or CD7 on dermal T cells NA Any 1 *Lymphoid atypia is defined as cells with enlarged hyperchromatic nuclei and irregular or cerebriform nuclear contours. Not applicable since it cannot fulfill any major criteria. +Pimpinelli N, Olsen EA, Santucci M, et al for the International Society for Cutaneous Lymphoma. Defining early mycosis fungoides. J Am Acad Dermatol Dec; 53(6):

18 Folliculotropic MF and Alopecia Mucinosa Kreibech (1925); follicular mucin in a patient with wide spread plaques some of which were clinically similar to Brocq s large plaque parapsoriasis Pinkus (1957): 6 patients.. follicular papules and/or indurated plaques that demonstrate (mucin) in the hair follicles that lead to hair loss Kim and Winkelmann (1962); 10 patients one of whom had lesions of LPP and later developed MF Pinkus (1964): Follicular mucinosis: Idiopathic Lymphoblastoma seconday follicular mucinosis Alopecia mucinos transforming to lymphoblastoma Pinkus (1983): several patients >plaques/tumors of MF Pinkus H. Alopecia mucinosa. Inflammatory plaques with alopecia characterized by rootsheath mucinosis. Arch Dermatol Arch Dermatol. Aug 1983;119(8):690 7

19 Follicular mycosis fungoides, a distinct disease entity with or without associated follicular mucinosis: a clinicopathologic and follow up study of 51 patients. van Doorn R, Scheffer E, Willemze R. Arch Dermatol. 2002;138(2): Lesions from all 51 patients showed follicular mucinosis Not possible to distinguish follicular MF with follicular mucinosis from follicular MF without follicular mucinosis Follicular mucinosis: a critical reappraisal of clinicopathologic features and association with mycosis fungoides and Sézary syndrome. Cerroni L, Fink Puches R, Bäck B, Kerl H. Arch Dermatol. 2002;138(2): Idiopathic follicular mucinosis may be a localized form of MF

20 Alopecia mucinosa is mycosis fungoides! Böer A, Guo Y, Ackerman AB. Am J Dermatopathol Feb;26(1): we propose a concept, and a terminology that derives from it, that synthesizes all that is known now about "alopecia mucinosa" and "follicular mucinosis," in particular the relationship of "alopecia mucinosa" to mycosis fungoides, including "follicular," "syringotropic," and erythrodermic manifestations of it. In short, we affirm that so called alopecia mucinosa is but one of many morphologic manifestations of mycosis fungoides. Epithelial mucinosis : deposits of mucin in infundibular, follicular and sebaceous epithelium; seen in host of conditions MF with epithelial mucinosis : fulfills criteria for MF clinically and histologically in addition to epithelial deposits of mucin

21 Folliculotropic MF Lacks characteristic patches/plaques Preferential involvement of head/neck region and presents as follicular papules, plaques and tumors Hair loss and secondary bacterial infections Severe pruritus Less amenable to local therapy More often large cell transformation and peripheral blood involvement Prognosis less favorable than classical MF (5 year survival 75% similar to tumor stage)

22 Folliculotropic MF Perivascular and periadnexal localization of dermal infiltrates of atypical lymphocytes T cell phenotype as in classical MF CD3+, CD4+, CD8, Admixed CD30+ cells Follicular mucinosis is present in most cases but not a prerequisite Folliculotropism and syringotropism (adnexotropism) instead of epidermotropism Keep in mind: 1/3 of cases of classic MF show eccrine gland involvement 1/2 of cases of classic MF show follicular involvement

23 Granulomatous MF and Granulomatous Slack Skin Ackerman AB, Flaxman BA. Granulomatous mycosis fungoides. Br J Dermatol 1970;82:397 An unusual form of mycosis fungoides was characterized clinically by the spontaneous resolution of ulcerated nodular lesions into poikiloderma and histologically by a granulomatous malignant lymphoma. a patient with widespread plaques and nodules of mycosis fungoides, and findings histopathologic of that lymphoma coupled with granulomas in the dermis of sections of tissue of several biopsy specimens. They termed the phenomenon granulomatous mycosis fungoides 1968 Bazex et al. described a clinical form similar to cutis laxa as 'Besnier Boeck Schaumann disease In 1978 Ackerman added the term 'granulomatous slack skin disease

24 Granulomatous MF versus GSS Granulomatous slack skin (GSS), however, does not appear to be merely mycosis fungoides (MF) associated with local elastic tissue destruction...a clinical presentation different from that of MF appears to be characteristic...a few patients with MF have shown granulomatous inflammation associated with the lymphomatous infiltrate, a process that has been termed granulomatous MF. LeBoit PE et al. Granulomatous slack skin: clonal rearrangement of the T cell receptor gene is evidence for the lymphoproliferative nature of a cutaneous elastolytic disorder. J Invest Dermatol 1987;89: GSS is a form of cutaneous lymphoma with an indolent but relentless course. It is characterized by circumscribed areas of pendulous lax skin that contain clonal infiltrates of helper T cells, which infiltrate the epidermis in a manner similar to that of mycosis fungoides and attract a granulomatous component that mediates massive dermal elastolysis. LeBoit PE Granulomatous slack skin. Dermatol Clin 1994; 12: Granulomatous inflammation in mycosis fungoides is a phenomenon that develops secondary to the lymphoma, and can be seen in such disparate representations of mycosis fungoides as parapsoriasis en plaques and granulomatous slack skin. Ackerman AB et al. Histologic Diagnosis of Inflammatory Skin Diseases. 2nd ed. 1997:842, 850.

25 Granulomatous MF/GSS In 1997 and 2005 'granulomatous slack skin' was included in the EORTC and then the WHO EORTC classification as a provisional entity. GSS Rare subtype with a striking clinical picture Granulomatous T cell infiltrates and loss of elastic fibers lead to asymptomatic skin wrinkles and slow development of lax skin, mainly in the flexures (axillae and groin) May be preceded by erythematous scaling patches or macules, and may coexist with classical MF lesions. In 33 50% of cases coexistence with Hodgkin lymphoma or nodal non Hodgkin lymphoma The pathogenesis of granuloma formation in lymphoma is unknown but its occurrence is not specific for MF

26 MF Large cell transformation Large cells >25% of total infiltrate or microscopic nodules of large cells with or without expression of CD % incidence Associated with poor prognosis Median survival months 5 year 11 32% Prognostic factors % of large cells CD30 expression Folliculotropism Stage Extent of skin involvement

27 Fig 2 MF LCT vs CD30+ALCL US Cutaneous Lymphoma Consortium algorithm for the classification of skin tumors in patients with CTCL Source Journal of the American Academy of Dermatology 2014; 70: (DOI: /j.jaad ) Copyright 2014 American Academy of Dermatology, Inc. Terms and Conditions

28 Sézary Syndrome Erythroderma Hyperkeratosis of palms and soles Generalized lymphadenopathy Clonal T cells (Sézary cells) in skin, lymph nodes, and peripheral blood (No history of MF) Similar phenotype as MF 5 year survival 20 30% Skin biopsy: +/ Similar histology as MF

29 Erythrodermic CTCL International Society of Cutaneous Lymphoma Concensus definitions and terminology Sezary syndrome (leukemic phase E CTCL) Erythrodermic mycosis fungoides in patients with MF (Secondary E CTCL) E CTCL, NOS

30 Update on Erythrodermic Cutaneous T cell Lymphoma: report of the International Society for Cutaneous Lymphoma The hematologic criteria recommended for Sézary syndrome are intended to identify patients with a worse prognosis compared with the other E CTCL subsets and consist of one or more of the following: (1) an absolute Sézary cell count of 1000 cells/mm3 or more; (2) a CD4/CD8 ratio of 10 or higher caused by an increase in circulating T cells and/or an aberrant loss or expression of pan T cell markers by flow cytometry; (3) increased lymphocyte counts with evidence of a T cell clone in the blood by the Southern blot or polymerase chain reaction technique; or (4) a chromosomally abnormal T cell clone Vonderheid EC, Bernengo MG, Burg G. J Am Acad Dermatol Jan;46(1):

31 MF versus SS Both MF and SS: Monoclonal population of CD4+/CD45RO+ helper T cells Loss of mature T cell antigens Involve skin (and other organs) Erythrodermic MF: Preceded by typical patch/plaque lesions Skin biopsy shows classical features of MF Absent or low circulating neoplastic cells SS Distinctive erythrodermic CTCL with hematologic evidence of leukemic involvement Skin biopsy may be non specific (in >30%); cells monomorphous, epidermotropism may be absent Not preceded by clinically typical MF

32 SS is a distinct entity and not merely a leukemic phase or variant of MF Differential Expression of Programmed Death 1 (PD 1) in Sézary Syndrome and Mycosis Fungoides Çetinözman F, Jansen PM, Maarten H, Vermeer, MH, Willemze, R. Arch Dermatol. 2012;148(12): Sezary syndrome and mycosis fungoides arise from distinct T cell subsets: a biologic rationale for their distinct clinical behaviors. Campbell JJ, Clark RA, Watanabe R et al. Blood. 2010; 116(5):

33 ISCL/EORTC Clinical Staging System for Mycosis Fungoides and Sézary Syndrome* Stage I Disease confined to the skin with patches/papules/plaques <10% (1A) or >10% (1B) of skin surface, N0 II Skin involvement with patches /papules/plaques associated with early (N1 N2) lymph node involvement (IIA) or skin involvement with tumors (>1cm) (IIB) III Erythroderma, +/ lymph node involvement (N0, N1, N2) and absent or low blood tumor burden (<1000/μl circulating Sézary cells) IV High blood tumor burden (>1000/μl circulating Sézary cells) and/or extensive lymph node involvement (N3) or visceral involvement (M1) * 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(6):

34 Mycosis Fungoides References 1. Willemze R, Jaffe ES, Burg G et al. WHO EORTC classification for cutaneous lymphomas. Blood. 2005; 105 (10): Song SX, Willemze R, Swerdlow SH et al. Mycosis fungoides. Am J Clin Pathol 2013;139: Lutzner M, Edelson R, Schein P et al. Cutaneous T cell lymphomas: The Sezary syndrome, mycosis fungoides and related disorders. Ann Intern Med. 1975; Sanchez JL, Ackerman AB. The patch stage of mycosis fungoides. Criteria for histologic diagnosis. Am J Dermatopathol. 1979; 1(1): Pimpinelli N, Olsen EA, Santucci M, et al for the International Society for Cutaneous Lymphoma. Defining early mycosis fungoides. J Am Acad Dermatol Dec; 53(6): Review 6. King Ismael D, Ackerman AB. Guttate parapsoriasis/digitate dermatosis (small plaque parapsoriasis) is mycosis fungoides. Am J Dermatopathol. 1992; 14(6):518 30; discussion Howard MS, Smoller BR. Mycosis fungoides: classic disease and variant presentations. Semin Cutan Med Surg. 2000;19(2): Ackerman AB, Flaxman BA. Granulomatous mycosis fungoides. Br J Dermatol 1970;82: LeBoit PE, Zackheim HS, White CR Jr. Granulomatous variants of cutaneous T cell lymphoma. The histopathology of granulomatous mycosis fungoides and granulomatous slack skin. Am J Surg Pathol. 1988; 12(2): 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(2): Cerroni L, Fink Puches R, Bäck B, Kerl H. Follicular mucinosis: a critical reappraisal of clinicopathologic features and association with mycosis fungoides and Sézary syndrome. Arch Dermatol. 2002;138(2): Böer A, Guo Y, Ackerman AB. Alopecia mucinosa is mycosis fungoides. Am J Dermatopathol. 2004;26(1):33 52.

35 13. Lehman JS, Cook Norris RH, Weed BR, et al. Folliculotropic mycosis fungoides: single center study and systematic review. Arch Dermatol. 2010;146(6): Pileri A, Facchetti F, Rütten A, et al. Syringotropic mycosis fungoides: a rare variant of the disease with peculiar clinicopathologic features. Am J Surg Pathol. 2011;35(1): Haghighi B, Smoller BR, LeBoit PE, et al. Pagetoid reticulosis (Woringer Kolopp disease): an immunophenotypic, molecular, and clinicopathologic study. Mod Pathol. 2000; 13(5): Werner B, Brown S, Ackerman AB. "Hypopigmented mycosis fungoides" is not always mycosis fungoides! Am J Dermatopathol. 2005; 27(1): Review. 17. Castano E, Glick S, Wolgast L, et al. Hypopigmented mycosis fungoides in childhood and adolescence: a long term retrospective study. J Cutan Pathol. 2013;40(11): Benner MF, Jansen PM, Vermeer MH, Willemze R. Prognostic factors in transformed mycosis fungoides: a retrospective analysis of 100 cases. Blood Feb 16;119(7): Kadin ME, Hughey LC, Wood GS. Large cell transformation of mycosis fungoides differential diagnosis with implications for clinical management: A consensus statement of the US Cutaneous Lymphoma Consortium. J Am Acad Dermatol Feb;70(2): 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(5): Çetinözman F, Jansen PM, Maarten H, Vermeer, MH, Willemze, R Differential Expression of Programmed Death 1 (PD 1) in Sézary Syndrome and Mycosis Fungoides. Arch Dermatol. 2012;148(12): Whittaker S, Knobler R Ortiz P et al. Major achievements of the EORTC Cutaneous Lymphoma Task Force (CLTF). European Journal of Cancer Supplements. March 2012; 10(1): Jawed SI, Myskowski PL, Horwitz S, et al. Primary cutaneous T cell lymphoma (mycosis fungoides and Sézary syndrome): Part I. Diagnosis: Clinical and histopathologic features and new molecular and biologic markers. J Am Acad Dermatol Feb;70(2):205.e1 205.e16. doi: /j.jaad

36 24. Jawed SI, Myskowski PL, Horwitz S, et al. Primary cutaneous T cell lymphoma (mycosis fungoides and Sézary syndrome): Part II. Prognosis, management, and future directions. J Am Acad Dermatol Feb;70(2):223.e1 223.e Willemze R. Thirty years of progress in cutaneous lymphoma research. G Ital Dermatol Venereol Dec;147(6): Review. 26. 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 Sep 15;110(6):