Mycosis Fungoides (and Subtypes)



Mycosis Fungoides (and Subtypes)


Sa A. Wang, MD





Key Facts


Terminology



  • Primary cutaneous T-cell lymphoma characterized by



    • Epidermotropism


    • Clinical course showing stepwise evolution of patches, plaques, and tumors


Clinical Issues



  • Overall indolent clinical course


  • Clinical stage is most important predictor of prognosis


Microscopic Pathology



  • Skin biopsy findings may be nondiagnostic in premycotic and some early patch stage lesions


  • Superficial band-like or lichenoid infiltrate in patch and thin plaque stage


  • Dense, band-like infiltrate in thick plaque stage


  • Nodular dermal infiltrate in tumor stage


  • Neoplastic lymphocytes are small, slightly cerebriform, and some have halos


  • Large cell transformation: Large cells are ≥ 25%


Ancillary Tests



  • Immunophenotype



    • CD3(+), TCR-αβ/βF1(+)


    • CD4(+), CD8(−), CD5(+/−), CD7(−), CD26(−)


Top Differential Diagnoses



  • Drug reactions, inflammatory dermatoses


  • Primary cutaneous CD30(+) T-cell lymphoproliferative disorders (LyP and ALCL)


  • Primary cutaneous γ/δ T-cell lymphoma


  • Primary cutaneous aggressive epidermotropic CD8(+) cytotoxic T-cell lymphoma







The plaque stage of mycosis fungoides shows the presence of multiple red plaques on much of the body surface of this patient.






The plaque stage of mycosis fungoides shows the presence of a Pautrier microabscess image containing small atypical tumor cells.


TERMINOLOGY


Abbreviations



  • Mycosis fungoides (MF)


Definitions



  • Primary cutaneous T-cell lymphoma characterized by



    • Epidermotropism


    • Clinical course showing stepwise evolution of patches, plaques, and tumors


ETIOLOGY/PATHOGENESIS


Unknown



  • Chronic antigenic stimulation, possibly due to infectious agent, may play a role


  • Genetic abnormalities are likely to be involved


CLINICAL ISSUES


Epidemiology



  • Incidence



    • 0.6/100,000 people per year


    • 50% of all cases of primary cutaneous lymphoma


  • Age



    • Adults, 5th-6th decade


    • Can be seen in patients < 35 years


  • Gender



    • M:F = 2:1


  • Ethnicity



    • Incidence is 1.7x higher in African-Americans than in whites


Presentation



  • Premycotic period



    • Nonspecific skin lesions; often slight scaling, pruritus



      • Lesions can wax and wane for years; may never progress to MF


      • Skin biopsy findings are nondiagnostic


  • Stepwise evolution of disease with appearance of patches, plaques, and tumors



    • Patches



      • Mostly on trunk, but can arise anywhere on body, including palms and toes


      • Can be associated with alopecia


    • Plaques



      • Palpable lesions rise above skin surface


      • Can be associated with patch lesions


    • Tumors



      • Usually manifest as skin nodule(s)


      • Can coexist with patches and plaques


  • MF variants



    • Pagetoid reticulosis (localized)



      • Also referred to as Woringer-Kolopp disease


      • Solitary, slow-growing, psoriasiform, crusty or hyperkeratotic patch or plaque


      • Often arises on distal limb


    • Folliculotropic (pilotropic) MF



      • Often involves head and neck area


      • Follicular papules (often grouped), alopecia, and acneiform lesions


      • Clinically more aggressive than other MF types; responds less well to skin-directed therapy


    • Syringotropic MF



      • Solitary, well-circumscribed, red-brown plaque, often associated with alopecia


      • Skin-directed therapy may be inadequate (similar to folliculotropic MF)


    • Granulomatous slack skin



      • Circumscribed areas of pendulous folds of lax skin in intertriginous areas (axillae, groin)


      • May coexist with classical MF lesions or classical Hodgkin lymphoma


Laboratory Tests



  • Morphologic assessment of peripheral blood for Sézary cells



    • Insensitive



  • Flow cytometry immunophenotypic analysis



    • Aberrant T-cell immunophenotypes support involvement by MF


  • Assessment of T-cell clonality by PCR


  • Serum lactate dehydrogenase &/or β-2-microglobulin



    • High levels associated with poorer prognosis


Natural History



  • Evolution from patches to plaques to tumors over time


  • Some patients develop visceral involvement by MF



    • Most common sites: Lungs, liver, spleen


Treatment



  • Early-stage disease (stages I and IIA): Direct skin therapy



    • Topical chemotherapy with nitrogen mustard or carmustine


    • Topical corticosteroids and retinoids


    • Phototherapy; local radiation (radiograph or electron beam)


  • Advanced-stage disease (stages IIB-IV)



    • Extracorporeal photopheresis


    • Single-agent chemotherapy



      • Methotrexate, pegylated liposomal doxorubicin (Doxil), purine analogs (fludarabine, 2-deoxycoformycin), others


    • Combination chemotherapy: Many regimens have been used



      • Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)


      • Cyclophosphamide, vincristine, and prednisone (CVP)


      • CVP with methotrexate (COMP)


    • Hematopoietic stem cell transplantation


Prognosis



  • Indolent clinical course overall


  • Disease prognosis depends on clinical stage


  • Clinical significance of T-cell receptor (TCR) gene rearrangements in MF staging is controversial



    • Monoclonal TCR gene rearrangement in blood is extremely common in early-stage disease



      • Not synonymous with blood involvement by MF in absence of morphologic or immunophenotypic evidence of disease


    • Monoclonal TCR gene rearrangement in lymph nodes is a common finding



      • Not prognostically significant in multivariate analysis


MACROSCOPIC FEATURES


General Features



  • Patches



    • Circumscribed lesions with discoloration of variable size, color, and shape


    • Little scaling, not palpable


  • Plaques



    • Palpable infiltrate of variable stage (thin and thick)


  • Tumors



    • Often exophytic and ulcerated (hence, term “fungoides”)


MICROSCOPIC PATHOLOGY


Histologic Features of Skin



  • Premycotic stage



    • Biopsy findings are typically nondiagnostic


    • Lymphocytic infiltrate



      • Mainly in upper dermis, not in subepidermal zone


      • Lacks obvious epidermotropism


  • Patch and early (thin) plaque stage



    • Superficial band-like or lichenoid infiltrate of lymphocytes and histiocytes



      • Atypical lymphocytes often line up along the basilar layer, especially at tips of rete ridges


      • Epidermotropism by single cells


      • Neoplastic lymphocytes are small, slightly cerebriform, some with halos


    • Other changes



      • Mild acanthosis, hyperkeratosis; basal layer damage



      • Edema and fibrosis, increased postcapillary venules


    • In some early lesions, biopsy findings may be nondiagnostic


  • Thick plaque stage



    • Dense, subepidermal, band-like infiltrate with many cerebriform lymphocytes


    • Epidermotropism is more prominent with



      • Intraepidermal clusters and Pautrier microabscesses


      • Confluent Pautrier microabscesses that can result in subcorneal and subepidermal bullae


  • Tumor stage



    • Dermal infiltrate becomes more diffuse and prominent



      • Tumor cells range in size from small to large


    • Epidermotropism may be lost


    • Large cell transformation



      • Often occurs in tumor stage


      • Large cells comprise ≥ 25% of tumor


      • CD30 can be (+); high proliferation rate (Ki-67)


  • MF variants



    • Pagetoid reticulosis



      • Marked intraepidermal proliferation of T cells


      • Sponge-like disaggregation of epidermis


      • Atypical cells have medium or large-sized, sometimes hyperchromatic and cerebriform nuclei


      • CD4(+), CD8(−), or CD4(−), CD8(+)


      • Often CD30(+); Ki-67 > 30%


    • Folliculotropic MF (pilotropic MF)



      • Atypical lymphocyte infiltrating epithelium of hair follicles


      • Infiltrate often spares epidermis


      • Often associated with mucinosis (mucinous degeneration)


    • Syringotropic MF



      • Hyperplastic eccrine ducts and glands infiltrated by atypical lymphocytes


      • Often abundant eosinophils present


    • Granulomatous slack skin



      • Dense granulomatous dermal infiltrate containing atypical T cells, macrophages, and often many multinucleated giant cells


      • Infiltrate often shows destruction of elastic tissue; ± epidermotropism


      • CD4(+), CD8(−)


Histologic Features of Lymph Nodes



  • Best to biopsy lymph nodes draining area of involved skin or node with highest standardized uptake value on FDG PET scan


  • Early involvement by MF (N1 and N2)



    • LN architecture is well-maintained


    • Dermatopathic changes common


    • Cerebriform lymphocytes are either absent, singly scattered, or in small clusters or aggregates



      • Often difficult to identify morphologically


  • Ancillary testing is important to demonstrate involvement by MF



    • Flow cytometric immunophenotyping


    • Assessment for TCR gene rearrangement


  • Extensive involvement by MF (N3)



    • Overt involvement or complete effacement of architecture


    • May show large cell transformation


Cytologic Features



  • Small- to medium-sized lymphocytes (unless large cell transformation)


  • Cerebriform nuclear contours and hyperchromatic nuclei


ANCILLARY TESTS


Immunohistochemistry



  • CD4(+), CD8(−)



    • Rare cases can be CD4(−), CD8(+) or CD4(+), CD8(+)


  • CD2(+), CD3(+), CD5(+), βF1(+)


  • Often shows CD7 loss (all disease stages)


  • CD45/LCA(+), CLA(+), CD52(+), CD25(−/+)


  • CD30(+/−), usually expressed by large cells


  • Ig(−), B-cell antigens(−)


Flow Cytometry



  • Can be performed on skin, peripheral blood, lymph nodes, and other tissue specimens


  • Flow panel should include



    • CD2, CD3, CD4, CD5, CD7


    • CD8, CD25, CD26, TCR-αβ, TCR-γδ


  • CD4:CD8 ratio is often increased


  • Typical immunophenotype: CD3(+), CD4(+), CD8(−), CD5(+), TCR-αβ(+)


  • Frequent immunophenotypic aberrancies



    • CD26(−), loss of CD7


    • Dim expression of CD2, CD3, CD4, or CD5


  • Clonality assessment by Vβ analysis



    • Can be used to follow treatment response


Molecular Genetics

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Mycosis Fungoides (and Subtypes)

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