1. MYCOSIS FUNGOIDES SHEIKHA MYCOSIS FUNGOIDES

2. Professor Anwar Sheikha MD, FRCP, FRCPath., FCAP, FRCPA, FRCPI, FACP Senior Consultant Clinical & Lab. Hematologist Clinical Professor of Hematology University of Mississippi Medical Center, Jackson, Mississippi Professor of Hematology, University of Salahaddin, Erbil, Kurdistan, IRAQ Owner & C.E.O., Raziana Company for Health Services, Hawler, IRAQ

3. MYCOSIS FUNGOIDES SHEIKHA MF is a cutaneous lymphoma of mature CD4 + T cells The commonest cutaneous T-cell lymphoma It has unique clinical & histologic features Not all cutaneous T-cell lymphomas are MF MYCOSIS FUNGOIDES SEZARY SYNDROME MF/SZ

5. MYCOSIS FUNGOIDES SHEIKHA Professor Lennert, Keil Classification

6. MYCOSIS FUNGOIDES SHEIKHA

7. W.H.O. CLASSIFICATION OF LYMPHOID NEOPLASMS Nodular Lymphocyte-Predominant Hodgkin Lymphoma Classical Hodgkin Lymphoma B T & NK HD Precursor B-cell neoplasms Mature (Peripheral) B-cell neoplasms Precursor T-cell neoplasms Mature (Peripheral) T-cell neoplasms NHL *

8. W.H.O. CLASSIFICATION OF LYMPHOID NEOPLASMS T & NK Mature (Peripheral) T-cell neoplasms NHL *T-cell Prolymphocytic Leukemia *T-cell Granular Lymphocytic Leukemia *Aggressive NK-cell Leukemia *Adult T-cell Leukemia/Lymphoma (HTLV1) *Extranodal NK/T-cell Lymphoma. Nasal type *Entropathy-type T-cell Lymphoma *Hepatosplenic γδ T-cell Lymphoma *Subcutaneous Panniculitis-like T Lymphoma *Mycosis Fungoides /Sézary Syndrome *Anaplastic Large-cell Lymphoma/T/null, skin type *Peripheral T-cell Lymphoma, not otherwise characterized *Angioimmunoblastic T-cell Lymphoma *Anaplastic Large-cell Lymphoma/T/null, systemic type *

9. MYCOSIS FUNGOIDES SHEIKHA

10. Incidence: 3 per million (0.29 per 100,000 population in USA) 2% of all new cases of NHL Age: Older adults (55 to 60) Male/Female: 2/1 PATCH STAGE PLAQUE STAGE TUMOR STAGE ERYTHRODERMA “ SEZARY ” Epidermo - tropism Cerebriform “ Sezary ” Cells

11. MYCOSIS FUNGOIDES SHEIKHA Patch Plaque Tumor Stage Sézary Syndrome MF patches are usually distributed in sun- shielded areas such as those covered by a bathing suit or intertriginous regions.

12. Various Cutaneous Manifestations of Mycosis Fungoides

13. MYCOSIS FUNGOIDES SHEIKHA The cardinal features of MF is infiltration of epidermis and then dermis by Atypical Cerebriform Lymphoid Cells EPIDERMOTROPIC

14. Girardi M et al. N Engl J Med 2004;350:1978-1988 Mycosis Fungoides: A Cancer of Skin-Homing T Cells

15. Multiple discrete & confluent plaques of cutaneous T-cell lymphoma “MF”

16. Multiple plaques of cutaneous T-cell lymphoma with tumor formation “MF”

17. 1.PATCH STAGE Mild epidermal hyperplasia with perivascular or band-like infiltrate of small- to medium-sized atypical lymphocytes with cerebriform nuclear convolution. EPIDERMOTROPISM: Cerebriform lymphocytes exhibit epidermotropism and are arranged along the dermal-epidermal junction in a single-file pattern or scattered in the epidermis. Pautrier ’ s microabscesses are small intra-epidermal collections of cerebriform lymphocytes & are pathognomonic for MF. They might not be present in early stages of MF MF PATCHES Eczematoid

18. 2. PLAQUE STAGE: The density of the neoplastic cells within dermis increases Exaggerated epidermotropism Psoriasiform

19. 2. PLAQUE STAGE: The density of the neoplastic cells within dermis increases Exaggerated epidermotropism Psoriasiform Plaque Stage: A broad band-like cellular infiltrate in the upper dermis Pautrier

20. 3. TUMOR STAGE: VERTICAL GROWTH Very dense dermal infiltrate involving the full breadth of the dermis & extending to the subcutaneous fat. Epidermotropism diminishes Tumors could get infected  sepsis  death de novo tumor “ d ’ emblee ” ﺩﻮﻤﻪﻞ

21. ERYTHRODERMA Pathology similar to Patch stage but infiltrate is more sparse Generalized erythroderma with Sézary cells “ with cerebriform nuclei ” in blood of >1,000/uL  Sézary Syndrome ↑ CD4 to CD8 ratio >10:1 T-cell Receptor gene rearrangement

22. Intensely symptomatic from pruritus & scaling Usually have lymphadenitis Generalized erythroderma Lympha- denopathy Sézary cells S é zary Syndrome =

23. MYCOSIS FUNGOIDES SHEIKHA

26. Pautrier Abscesses

28. MYCOSIS FUNGOIDES SHEIKHA LYMPH NODE INVOLVEMENT IN MF or SZS DERMATOPATHIC LYMPHADENITIS = DL CATEGORY III “LN4” CATEGORY II “LN3” CATEGORY I “LN0-LN2” Partial or complete effacement of LN architecture by cytologically atypical lymphocyte Clusters of 10 or more atypical LC confined to the paracortex ± DL LN0 = DL/ No atypical LC LN1 = Scattered atypical cerebriform LC (not in clusters) ± DL LN2 = Small clusters < 6 cells ± DL

29. MYCOSIS FUNGOIDES SHEIKHA IMMUNOPHENOTYPE in MF/SZS CD2 + CD3 + CD4 + CD5 + CD25 -/+ CD7 - CD30 - Molecular Diagnosis: PCR of T-cell Receptor γ rearrangement, especially in early patch stages Cell of Origin: CD4 + T lymphocyte with skin homing “ epidermotropic ” properties

30. MYCOSIS FUNGOIDES SHEIKHA CLINICAL PRESENTATION OF MF MF often has a long natural history Median duration from onset to diagnosis may be 5 years or more Usually starts with scaly skin lesions that wax & wane over years Biopsy at this stage is usually non-diagnostic Patient may respond at this stage to topical steroid Repeated biopsy is warranted if MF is suspected and biopsy is negative

31. MYCOSIS FUNGOIDES SHEIKHA CLINICAL PRESENTATION OF MF 30% Limited patch or plaque stage <10% BSA T1 35-40% Generalized patch or plaque stage >10% BSA T2 15-20% Tumorous stage <10% BSA T3 15% Erythro- derma T4 PRURITUS Commonest symptom of MF Only 15% of MF patients show extracutaneous disease. Lymph nodes; Visceral disease, etc

32. MYCOSIS FUNGOIDES SHEIKHA OTHER FEATURES OF MF Skin Hair Follicles could be extensively infiltrated. Mucin might be deposited  Follicular MF Pagetoid reticulosis is a verrucous variant of MF Affecting acral sites like hands & feet. Extreme atypical LC epidermotropism  verrucae Granulomatous slack skin  pendulous folds of slack or lax skin “ macrophage-mediated destruction of dermal elastic fibers ” Many MF have only skin problems. 15% have extracutaneous disease; LN, Visceral sites “ Lung, Oral cavity, CNS, etc ” could be affected.

33. Various Cutaneous Manifestations of Mycosis Fungoides

34. MYCOSIS FUNGOIDES SHEIKHA STAGING OF MF

35. MYCOSIS FUNGOIDES SHEIKHA (SKIN)T Limited patch/plaque (<10% total skin surface) T1 Generalized patch/plaque (>10% total skin surface) T2 TumorsT3 Generalized Erythroderma T4 (LYMPH NODES) N LN Clinically uninvolved N0 Enlarged; histologically uninvolved (reactive & dermatopathic) N1 LN Clinically uninvolved; histologically involved N2 LN enlarged & involved N3 (VISCERA) M No Visceral involvement M0 Visceral involvement M1 (BLOOD) B No Sézary cells (<5% of LC) B0 Circulating Sézary cells (>5% of LC) B1 Tumor- Node- Metastasis- Blood Classification For MF

36. MYCOSIS FUNGOIDES SHEIKHA MNT Clinical stages M0N0T1IA M0NOT2IB M0N1T1-2IIA M0N0-1T3 tumor IIB M0N0T4IIIA Erythroderma M0N1T4IIIB Erythroderma M0N2-3 histology T1-4IVA M1N0-3T1-4IVB CLINICAL STAGING SYSTEM FOR MF B CLASSIFICATION (SEZARY CELLS) DOES NOT ALTER CLINICAL STAGE

37. MYCOSIS FUNGOIDES SHEIKHA (SKIN)T Limited patch/plaque (<10% total skin surface) T1 Generalized patch/plaque (>10% total skin surface) T2 TumorsT3 Generalized Erythroderma T4 (LYMPH NODES) N LN Clinically uninvolved N0 Enlarged; histologically uninvolved (reactive & dermatopathic) N1 LN Clinically uninvolved; histologically involved N2 LN enlarged & involved N3 (VISCERA) M No Visceral involvement M0 Visceral involvement M1 (BLOOD) B No Sezary cells (<5% of LC) B0 Circulating cells (>5% of LC) B1 MNTClinical stages M0N0T1IA M0NOT2IB M0N1T1-2IIA M0N0-1T3IIB M0N0T4IIIA M0N1T4IIIB M0N2-3T1-4IVA M1N0-3T1-4IVB Tumor-Node-Metastasis-Blood & Clinical Staging Classification

38. MYCOSIS FUNGOIDES SHEIKHA

39. TOPICAL CHEMO- THERAPY TREATMENT OF MF TOPICAL NITROGEN MUSTARD “ MECHLORETHAMINE" Effective Mechanism ?? OINTMENT AQUEOUSSOLUTION 10 to 20 mgPer 100 cc = Choice of aqueous or ointment depends on convenience, preference & cost Hypersensitivity is 30% with Aqueous solution & < 5% with ointment

40. MYCOSIS FUNGOIDES SHEIKHA Topical N 2 -Mustard is applied locally or to the entire skin at least daily during the clearing phase. After few weeks treatment may be applied to the affected region. N2-Mustard may only be applied to the affected anatomical site if the disease is really limited. Treatment is continued on daily basis until the lesions are cleared (6 months+)  3 to 6 months of maintenance therapy If response is slow; increase N 2- Mustard concentration or frequency of application CR rate for limited patch or plaque stage “ T1 ” is 70% to 80% The median time to skin clearance is 6 to 8 months 20% to 25% have durable CR of > 10 years Local Radiation to Refractory local lesions Half will relapse after discontinuation of R/ but respond again

41. MYCOSIS FUNGOIDES SHEIKHA TOPICAL CHEMO- THERAPY TREATMENT OF MF TOPICAL Carmustine “ BCNU" Similar efficacy to N 2 - Mustard but it could be absorbed & cause myelosuppression, thus limiting its long-term use. BCNU use could cause telangiectasias in areas exposed to the drug

42. MYCOSIS FUNGOIDES SHEIKHA PHOTO- THERAPY TREATMENT OF MF Ultraviolet Light (UV)  UVA or UVB wavelength ± Psoralen = PUVA Psoralen is a photosensitizing agent The long-wave UVA has greater dermal penetration power For early Limited disease UVB alone or Home UV phototherapy (UVA & UVB) could be effective PUVA is the most commonly used form of therapy for MF & SZS It is effective in Psoriasis but has also been found to be effective in MF PUVA is used 2-3 times/week during the clearance phase ( >6 months) Reduce frequency in maintenance phase. For recurrence ↑ frequency again Complete clearance rate with PUVA is 50% to 90% for patch & plaque stage Less response for erythrodermic or tumor stage

43. MYCOSIS FUNGOIDES SHEIKHA PUVA COMPLICATIONS ACUTE: Nausea Phototoxic reactions such as erythroderma, blistering & dryness Shield eyes & skin from sun for 24 hrs after Psoralen ingestion LONG TERM: Cataract (use UVA opaque goggles during therapy) Secondary cutaneous malignancy

44. MYCOSIS FUNGOIDES SHEIKHA TOPICAL RETINOIDS Bexarotene “ Targretin ” 1% Gel Overall Response Rate is 63% Complete Response rate is 21% Because of the irritant effect, it is only used for discrete patch or plaque stage Not applicable in generalized disease Apply thin over the lesions twice daily Irritation is a rule. Withhold for few weeks if erythema

45. MYCOSIS FUNGOIDES SHEIKHA RADIATION THERAPY TREATMENT OF MF MF is an exquisitely radiosensitive neoplasm Irradiation may be exploited in several ways Individual plaques or tumors of MF may be treated to total doses of 15 to 25 Gy in 1 to 3 weeks, with a high likelihood of achieving long-term local control. For the unusual patient with with unilesional or localized MF, local electron beam therapy achieves the most efficient & complete clearance of the disease Depth of penetration of electrons is controllable; this is of major advantage in MF Depth of R/ with TSEBT is better than N 2 -Mustard or PUVA

46. MYCOSIS FUNGOIDES SHEIKHA TOTAL SKIN ELECTRON BEAM THERAPY “Stanford Technique” OVERALL RESPONSE RATE 100% COMPLETE RESPONSE RATE 98% 50% OF T1 & 25% OF T2 ARE FREE OF DISEASE 5 YEARS AFTER A SINGLE COURSE A full cycle takes 2 days 2 Gy is given per cycle Total dose of around 36 Gy is given over 10 weeks; Give a week rest in middle to give relief from erythema Indications : Very thick plaques Recent rapid progression Other local therapy are ineffective Local N 2 -Mustard is indicated for 6 months after TSEBT Complications : Erythema Dry desquamation Alopecia Nail loss Sweating problems

47. MYCOSIS FUNGOIDES SHEIKHA

48. SYSTEMIC CHEMO- THERAPY TREATMENT OF MF Only for Extracutaneous MF 80% to 100% Complete or Partial Response Duration of Response is usually < 1 year CHOPCOPCAVECOMP

49. MYCOSIS FUNGOIDES SHEIKHA OTHER TREATMENTS TREATMENT OF MF Extracorporeal Photopheresis Interferon-α Systemic Retinoids Recombinant Fusion Proteins IL-2-diphtheria toxin (Ontak; denileukin diftitox) For IL-2 receptor “CD25 + ” MF

50. MYCOSIS FUNGOIDES SHEIKHA

51. OUTCOME STAGE IA (Limited Patch or Plaque, T1) Disease Excellent Prognosis with conventional Treatment Life Expectancy = Age Matched Population Only 9% progress to more advanced stages Aggressive Therapy has no Survival Advantage Do not over treat

52. MYCOSIS FUNGOIDES SHEIKHA OUTCOME STAGE IB/IIA (Generalized Patch or Plaque, T2) Disease Median Survival of 11 years 25% MR from MF

53. MYCOSIS FUNGOIDES SHEIKHA OUTCOME STAGE IIB (Tumorous) Disease Median Survival of 3.2 years Majority die of MF

54. MYCOSIS FUNGOIDES SHEIKHA OUTCOME STAGE III (Erythrodermic, T4) Disease Total Skin Electron Beam Therapy is not recommended Survival is variable

55. MYCOSIS FUNGOIDES SHEIKHA OUTCOME STAGE IV (Extracutaneous) Disease Poor Prognosis Median Survival 13 months

56. MYCOSIS FUNGOIDES SHEIKHA REVISON

57. Various Cutaneous Manifestations of Mycosis Fungoides Panel A shows patch-or-plaque MF affecting the lower trunk. The patches are thin, slightly scaly, erythematous lesions typically greater than 4 cm in diameter and distributed in sun-shielded areas such as those covered by a bathing suit or intertriginous regions. Plaques are thicker than patches.

58. Various Cutaneous Manifestations of Mycosis Fungoides Panel B shows pagetoid reticulosis, a variant of mycosis fungoides that typically consists of a single patch or plaque located in an acral area.

59. Various Cutaneous Manifestations of Mycosis Fungoides Panel C shows syringotropic mycosis fungoides, which is manifested as papules 1 to 3 mm in diameter distributed in the eccrine ducts, indicating the propensity of lymphoma cells to accumulate in these locations.

60. Various Cutaneous Manifestations of Mycosis Fungoides Panel D shows follicular mycosis fungoides, in which lesions characterized by alopecia develop. In a similar variant, there is mucin deposition in the follicles.

61. Various Cutaneous Manifestations of Mycosis Fungoides Panel E shows hypopigmented mycosis fungoides. This variant is more noticeable in persons with dark pigmentation and may be more common in childhood and adolescence than in adulthood. Hypopigmentation to full depigmentation occurs in patches.

62. Various Cutaneous Manifestations of Mycosis Fungoides Panel F shows erythrodermic mycosis fungoides. This variant may evolve from patch-or-plaque mycosis fungoides and eventually involve more than 80 percent of the body-surface area. It may also arise spontaneously, as in the Sézary syndrome.

63. Various Cutaneous Manifestations of Mycosis Fungoides Panel G shows the Sézary syndrome. In its most florid form, the diffuse infiltration of the skin may produce the exaggerated facial lines, resulting in "leonine facies." The Sézary syndrome is also associated with atypical lymphocytes on the blood smear.

64. Various Cutaneous Manifestations of Mycosis Fungoides Panel H shows a mycosis fungoides tumor. Such tumors define the T3 stage of disease and may arise at the site of plaques or appear on their own, without being preceded by a patch-or-plaque lesion. The vertical growth phase is accelerated, and tumors tend to appear more quickly than plaques. Tumors not characterized by epidermotropism or previous mycosis fungoides are sometimes called "non–mycosis fungoides cutaneous T-cell lymphoma

65. Various Cutaneous Manifestations of Mycosis Fungoides Let me now examine you

66. MYCOSIS FUNGOIDES SHEIKHA THANK YOU

67. MYCOSIS FUNGOIDES SHEIKHA

71. Girardi M et al. N Engl J Med 2004;350:1978-1988 Therapeutic Options in the Management of Mycosis Fungoides and the Sezary Syndrome

72. MYCOSIS FUNGOIDES SHEIKHA Therapeutic Options in the Management of Mycosis Fungoides and the Sezary Syndrome

73. MYCOSIS FUNGOIDES SHEIKHA

80. ATCLL

81. Blood of a Cutaneous T-cell Lymphoma Patient showing Sézary cells

82. Pautrier microabscess

83. MYCOSIS FUNGOIDES SHEIKHA

86. Figure 2. Mycosis Fungoides: A Cancer of Skin-Homing T Cells. In cutaneous T-cell lymphoma, cells home to the skin by virtue of interactions with dermal capillary endothelial cells. Circulating lymphoma cells bearing cutaneous lymphocyte antigen (CLA) roll along endothelial cells expressing E-selectin. Chemokine receptors (e.g., CC chemokine receptor 4 [CCR4]) on the malignant T cells recognize chemokines (e.g., CC chemokine ligand 17 [CCL17]) that have emanated from the epidermis and bound to the luminal side of endothelial cells, greatly facilitating the binding of leukocyte-function–associated antigen type 1 on the lymphoma cells to intercellular adhesion molecule 1 on the endothelial cells and subsequent extravasation into the dermis. From there, the lymphoma cells often display an affinity for epidermal cells and cluster around Langerhans' cells, forming Pautrier's microabscesses, which can be observed on histologic examination. This process is principally guided by the interactions of lymphoma-cell integrin E 7, CCR4, and the CD4 T-cell receptor complex with E-cadherin, CCL22, and major-histocompatibility-complex class II (MHC-II) molecules, respectively. TCR denotes T-cell receptor.

87. MYCOSIS FUNGOIDES SHEIKHA

95. WHAT TO REMEMBER ABOUT MF It is an indolent troublesome disease Flat patches, thin plaques, deep tumors & Erythroderma Cerebriform cells Epidermotropism The patient has to live with it in the majority of cases

96. MYCOSIS FUNGOIDES SHEIKHA

101. TREATMENT OF MF SYMPTOMATIC: Pruritus & xerosis could be severe R/ Aggressive emolliation, topical steroid & oral antipruritics  Dermatologists MF TREATMENT: TOPICAL CHEMO- THERAPY PHOTO- THERAPY TOPICAL RETINOIDS RADIATION THERAPY SYSTEMIC CHEMO- THERAPY Extracorporeal Photopheresis Interferon –α Retinoids Recombinant Fusion Proteins Combined Modality Therapy

102. Mycosis fungoides Mycosis fungoides lymph node involvement

103. MYCOSIS FUNGOIDES SHEIKHA Plaque Stage: A broad band-like cellular infiltrate in the upper dermis

104. MYCOSIS FUNGOIDES SHEIKHA Patch Plaque Tumor Stage Sézary Syndrome