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Lymphoma - Non B cell neoplasms

T/NK cell disorders

Mycosis fungoides


Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 25 August 2013, last major update August 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Definition
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● Mycosis fungoides (MF) is an epidermotropic, primary cutaneous T-cell lymphoma (CTCL) characterized by infiltrates of small to medium-sized T lymphocytes with cerebriform nuclei (WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, Lyon 2008)

Terminology
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● Initially called pian fungoides (Jean-Louis Alibert, 1814), because it resembles yaws (caused by Treponema), which is also called pian
● Later renamed as mycosis fungoides, due to its resemblence to mushrooms
● Also called cutaneous T-cell lymphoma (not a good term since nonspecific as to histological type)

Epidemiology
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● Most common type of cutaneous T-cell lymphoma, almost 50% of all primary cutaneous lymphomas
● Adults/elderly, but also children and adolescents
● M:F ratio 2:1, black:white ratio 1.7
● Etiology unknown

Sites
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● Widespread cutaneous distribution but limited to the skin, as a rule
● Extracutaneous involvement may occur in advanced stages (lymph nodes, liver, spleen, lungs, blood, rarely bone marrow)

Clinical features
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● Multiple skin lesions, progressing stepwise from a scaly rash to patches to plaques to tumors
● Often misdiagnosed as psoriasis
● Erythrodermic stage is uncommon; lacks criteria for Sézary syndrome

Case reports
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● 14 year old boy and his 10 year old sister (Acta Derm Venereol 2007;87:529)
● 50 year old man with mycosis fungoides and subsequent Hodgkin lymphoma (Mod Pathol 2001;14:91)
● 75 year old man with recurrent Hodgkin lymphoma and diffuse large B-cell lymphoma (Acta Derm Venereol 2009;89:421)
● Lesions only in skin appendages of sun damaged skin (Hum Pathol 2003;34:1216)

Treatment and prognosis
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● Indolent (median survival 8 years) course with slow progression (years, decades) but may progress to Sézary syndrome
● Single most important prognostic factor is clinical stage
● Limited disease: excellent prognosis, survival similar to general population
● Adverse prognostic parameters: skin tumors, extracutaneous dissemination, >60 years of age, increased LDH, histologic transformation (>25% blast cells)
● Spreads to lymph nodes and bone marrow; 25% have peripheral blood involvement resembling Sézary syndrome
● Transformation to large T-cell lymphoma occurs occasionally as a terminal event; may be associated with hyperdiploidy
● Treatment: phototherapy or chemotherapy, topical therapy, radiotherapy

Postulated normal counterpart
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● Mature skin-homing CD4+ T-cell

Gross description
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● Patches, plaques, tumors, ulceration, erythroderma

Gross images
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Patches

   

Plaque

   

Tumor


Erythroderma

Micro description
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● See below for precursor lesions and variants
● T cells (small and large) in epidermis and upper dermis with cerebriform nuclei (marked infolding of nuclear membrane), Pautrier microabscesses in epidermis; minimal papillary dermal fibrosis, may have granulomas
● Patch stage: superficial band-like or lichenoid infiltrate, mainly lymphocytes and histiocytes, but also a few atypical cells (small/medium-sized, cerebriform nuclei, halo) usually confined to the epidermis (basal layer)
● Plaque stage: more pronounced epidermotropism with occasional characteristic intraepidermal collections of atypical cells (Pautrier microabscesses)
● Tumor stage: more diffuse dermal infiltrate, may lose epidermotropism, more size and shape variability of tumor cells, histologic transformation may occur (>25% large lymphoid cells in the dermal infiltrate)
● Uninvolved but enlarged lymph nodes frequently show dermatopathic lymphadenopathy
● Histologic staging for clinically abnormal lymph nodes (>1.5 cm): no involvement, early involvement, overt involvement (see staging of primary cutaneous lymphoma)
● Can screen for Mycosis fungoides or Sézary syndrome in peripheral blood using flow cytometry for CD26 negative or dim expression
● Tumor cells also have increased CD4/CD8 ratio and lower CD4 surface expression (Am J Clin Pathol 2001;115:885)
● CD8:CD3 ratio < 25% in epidermal component of lymphocytic infiltrate is supportive of diagnosis (Mod Pathol 2003;16:857)

Micro images
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Mycosis fungoides and Hodgkin’s lymphoma

   
Various images

       
Pautrier microabscesses


Halo lymphocytes

Positive stains
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● CD3 (but may be reduced, Am J Clin Pathol 2000;114:467), CD4 (usually)
● Variable CD2 and CD5 (Am J Clin Pathol 2010;134:739:)
● Also CD45RO, TCRβ, CLA, cytotoxic granules (rarely early, variable in advanced lesions)
● Rare cases are CD8+ (especially pediatric patients, same prognosis as CD4+ cases)

Negative stains
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● CD7, CD8, CD30

Genetics and Molecular
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● Clonal rearrangement of T cell receptor genes, but no specific chromosomal abnormalities
● Complex karyotypes especially in advanced stages
● Constitutive activation of STAT3 and inactivation of CDKN2A/p16 and PTEN may be associated with disease progression
● TNF anti-apoptotic pathway activation in tumorigenesis

Differential diagnosis
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● T cell cutaneous proliferative disorder with intraepidermal infiltrate of cells with cerebriform nuclei; solitary erythematosquamous patch with slow evolution; spongiotic dermatitis (also atypical lymphocytes in epidermis/dermis)
● In lymph nodes: peripheral T cell lymphoma-NOS, Hodgkin lymphoma


Precursor lesion - "parapsoriasis"
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● Chronic recalcitrant erythematous scaling lesions
● Benign form: parapsoriasis en plaques (Brocq disease), no malignant transformation
● Large plaque forms with or without poikiloderma (LPP) may evolve into mycosis fungoides or cutaneous T cell lymphoma (10-50%)
● Histology: subepidermal free zone, sparing of the papillary dermis, no significant epidermotropism
● TCRγ gene rearrangements may be clonal (50%) but have no prognostic significance


Variants of Mycosis fungoides
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Folliculotropic mycosis fungoides
● Follicular infiltrates of cerebriform CD4+ T lymphocytes
● Frequent sparing of the epidermis and interfollicular areas
● Mucinous degeneration of hair follicles (follicular mucinosis)
● Preferential head and neck involvement with grouped follicular papules and associated alopecia
● Less amenable to skin-targeted therapy due to deep localization (5 year survival 70-80%, worse than plaque stage)

               
Various images

Pagetoid reticulosis
● Patches/plaques with intraepidermal neoplastic T-cell proliferation and sponge-like disaggregation of the epidermis, typically on a distal limb
● Term used only for the localized type (Woringer-Kolopp), NOT for the disseminated one (Ketron-Goodman) currently classified as either aggressive epidermotropic CD8+ CTCL or cutaneous γδ TCL
● May be either CD4+/CD8- or CD4-/CD8+
● Often CD30+
● No reported extracutaneous dissemination or disease-related death

   

           
Various images

Granulomatous slack skin
● Extremely rare, indolent clinical course
● Slowly developing folds of lax skin (axillae, groin)
● Granulomatous infiltrate of clonal CD4+ T-cells, abundant macrophages and multinucleated giant cells
● Associated with classical Hodgkin lymphoma (one third of cases) and classical MF

           
Figure 1: axillary nodules
Figure 2: dense dermal mononuclear infiltrate
Figure 3: epithelioid and giant cell granuloma
Figure 4: CD4+

               
Various images

Hypopigmented variant
● Hypopigmentation occurs in the absence of classic lesions of mycosis fungoides
● Usually affects young people with dark complexions with childhood onset; otherwise similar history, prognosis and histology of classic form, although most were CD8+ (classic forms are CD8-, Am J Surg Pathol 2002;26:450)

Syringotropic variant
● Rare; solitary, well circumscribed red-brown plaque with hair loss
● Predominant involvement of irregularly proliferating eccrine sweat glands by cerebriform lymphocytes

Other variants: bullous, dyshidrotic, granulomatous, hyperkeratotic/verrucous, hyperpigmented, ichthyosiform, palmoplantar, pigmented purpura-like, poikilodermic, pustular, unilesional, vegetating/papillomatous

Additional references
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WHO Classification of Skin Tumours, Lyon 2006
● Review articles: Am J Surg Pathol 2000;24:40 (criteria for diagnosis), Am J Surg Pathol 2002;26:1259 (prominent granulomatous reaction), Am J Clin Pathol 2000;114:467 (diminished CD3 staining)

End of Lymphoma - Non B cell neoplasms > T/NK cell disorders > Mycosis fungoides


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