Mycosis Fungoides and Sézary Syndrome

Mycosis Fungoides (MF) and Sezary Syndrome.

Are You Confident of the Diagnosis?

• What you should be alert for in the history

Be observant for a patient who has had a long history of a questionable rash or a benign skin condition, particularly in areas of non–sun-exposed skin, unresponsive to medications indicated for that disease. The clinical course of mycosis fungoides (MF) is very indolent and can at times be mistaken for benign skin conditions such as chronic eczema, allergic contact dermatitis, or psoriasis. As a result, in these patients, it can take many years (median duration to diagnosis = 6 years) before an accurate diagnosis is made.

Sezary syndrome (SS) is classically defined as the triad of erythroderma, generalized lymphadenopathy, and the presence of malignant T-cells in the skin, lymph nodes, and peripheral blood. Patients usually present with an abrupt onset of itching and non-specific erythroderma. Rarely, patients have a preceding history of MF.

• Characteristic findings on physical examination

The initial skin lesions in MF will generally appear in sun-protected areas, including bathing trunk areas, and the insides of the arms. The clinical presentation is divided morphologically into patches, plaques and tumors.

Patches are characterized by variably sized, erythematous lesions, at times with fine overlying scale (Figure 1). They may have a “cigarette paper-like” appearance. In early phases, lesions can appear more “digitate.”

Figure 1.

Plaques are characterized by infiltrative, at times scaly, reddish-brown lesions that can become confluent. (Figure 2) These lesions can resemble psoriasis, a subacute dermatitis, or even a granulomatous process such as granuloma annulare, although MF typically has associated epidermal change (scale).

Figure 2.

Tumors are characterized by solitary, localized, or at times generalized lesions that can ulcerate (Figure 3). Patients may present with patches, plaques or tumors (Figure 4) which may ulcerate. Only rarely do tumors appear de novo (called d’emblee form). As a result, if only tumors are present without preceding or concurrent patches or plaques, consideration of a less common variant of cutaneous T-cell lymphoma (CTCL) should be made.

Figure 3.

Figure 4.

Patients who have erythema covering over 80% of their body surface area (BSA) (erythroderma) have a greater risk of leukemic involvement (Figure 5).

Figure 5.

Although patients may classically present with patch, plaque or tumor stage disease, there are many variants that may make a clinical diagnosis difficult. Some of these variants include: the classical form, hypopigmented, follicular, syringotropic, granulomatous (including granulomatous slack skin), palmo-plantar, pigmented purpuric-like, bullous/vesicular, interstitial, verrucous, vegetating, unilesional, erythrodermic, poikilodermatous, pustular, zosteriform and ichthysiform-like.

Folliculotropic MF: Patients can present with grouped follicular papules (Figure 6), acneiform lesions, including comedonal lesions, indurated plaques, and sometimes tumors. Lesions can be associated with alopecia given involvement of the hair follicle. The presentation may be more pronounced in the head and neck area, but lesions may occur anywhere on the skin surface. Pruritus may be very severe.

Figure 6.

SS by definition presents with erythroderma, which can be associated with exfoliation, edema, lichenification and intense pruritus. Patients may also commonly have lymphadenopathy, alopecia, onychodystrophy, ectropion, and palmoplantar hyperkeratosis.

Formal estimation of a patient’s cutaneous involvement is important to track disease burden and response to therapy. This can be done using a modified severity-weighted assessment tool (mSWAT). Patch, plaque and tumor body surface area (BSA) are determined and multiplied by a factor of 1, 2 and 4 respectively to establish their standardized mSWAT score.

In addition to accurate assessment of their skin lesions, patients should undergo palpation for lymphadenopathy and organomegaly. Lymph nodes greater than 1.5 cm in size that are firm, irregular, clustered or fixed, are of most concern.

• Expected results of diagnostic studies

Biopsy:

In order to confirm the diagnosis, a tissue biopsy is necessary, and if possible, of two distinct lesions with at least one representing a more indurated lesion. Patients should be off of topical steroids for at least two weeks prior to biopsy to enhance diagnostic yield. The histopathology may differ slightly with progressive disease. Early patch lesions can demonstrate a superficial bandlike or lichenoid infiltrate consisting of lymphocytes and histiocytes. Atypical cells with small to medium-sized cerebriform nuclei may be identified, and can be found in the epidermis (epidermotropism).

Another important diagnostic clue is the presence of atypical lymphocytes hugging the dermal, epidermal junction. A psoriasiform hyperplasia of the epidermis can be seen. The papillary dermis shows fibrosis with coarse bundles of collagen. Diagnostic clue: presence of epidermotropic lymphocytes in the basal layer of the epidermis and with nuclei slightly larger than those within the upper dermis.

In plaques, the epidermotropism can be more pronounced. The clustered atypical lymphocytes surrounding Langerhans cells present in the epidermis are called Pautrier microabscesses (Figure 7). There can be a dense band-like infiltrate within the upper dermis (Figure 8). Progression to tumor stage disease reveals dense, nodular or diffuse infiltrates which can involve all levels of the dermis. Epidermotropism may be lost. Angiocentricity and/or angiodestruction may exist. Transformation to a diffuse large cell lymphoma may occur (CD30+ or CD30-). It is defined as the presence of large cells exceeding 25% of the infiltrate or large cells forming microscopic nodules.

Figure 7.

Figure 8.

In SS, there is often a psoriasiform spongiotic pattern with a band-like infiltrate of lymphocytes (Figure 9).The infiltrate tends to be more monotonous. Although a lymphocytic infiltrate within the upper dermis is common, the typical findings of lymphocytes hugging the dermal, epidermal junction with or without epidermotropism may be absent in as many as 50% of cases, making the histologic diagnosis of SS quite difficult. However, the ultimate distinction from MF must be made via clinical correlation and other diagnostic features. In erythrodermic cases, it is always recommended that peripheral blood flow cytometry be performed (see below under Bloodwork).

Figure 9.

Folliculotropic MF is characterized histopathologically by folliculotropic infiltrates with relative sparing of the epidermis and evidence of follicular mucinosis. Occasionally the epidermis may also be involved. In some cases, there may be infiltration of both follicular epithelium and eccrine sweat glands.

Bloodwork:

Blood involvement is determined by flow cytometric analysis and detection of a clonal T-cell population. The typical immunophenotype of the abnormal peripheral blood T-cell population is CD3+, CD4+, CD7- (loss in about 50% of cases), CD26- (loss in more than 90% of cases), CD8-. Occasionally MF or SS can occur where the malignant population demonstrates a CD8+ phenotype. SS with the CD8 phenotype can be associated with retroviral infections (HTLV-1/2 or HIV), and it is recommended that these serologies be obtained.

For a diagnosis of SS, peripheral blood analysis must reveal one or more of these: absolute sezary count of more than 1000 cells/mm³, CD4:CD8 ratio greater than 10, loss of any or all of the T-cell antigens CD2, CD3, CD4 and CD5, loss of CD26 or CD7, in the setting of a positive T-cell clone. However, one should note that clonality may not be detected in early cases with the use of standard TCR/PCR (T-cell receptor gene rearrangement assays).

The malignant cells generally have a Beta-F1+(alpha/beta T-cell), CD3+, CD4+, CD5+, CD45RO+, CD8- phenotype. The ratio of CD4:CD8 can be greater than 4:1. The cells may lack expression of certain T-cell antigens such as CD7 and CD26.

Expression of cytotoxic proteins (TIA-1, granzyme B) are identified in 10% of patients with plaques, but is more common in tumors with blastic transformation.

Gene Rearrangement:

Tissue and blood may also be sent for T-cell receptor gene rearrangement by polymerase chain reaction (PCR). A clonal population is commonly identified in the skin of patients with plaque or tumors, but only in 50-60% of early patch stage disease. One should be aware that a dominant clone can also be identified in patients with autoimmune inflammatory dermatoses. With an equivocal flow cytometry result, it is important to be able to identify whether a clonal population exists in the peripheral blood and whether it matches with that in the skin, which is more suggestive of a diagnosis of some form of cutaneous T-cell lymphoma. A newer modality, high throughput sequencing of the T-cell receptor (HTS), may enhance diagnostic specificity and sensitivity aiding in a more accurate initial diagnosis and in the assessment of disease progression and minimal residual disease activity.

Radiologic studies:

Radiologic evaluation is not always necessary in patients, especially those with early stage disease. In patients with early stage disease including Stage IA or patients with limited T2 skin disease and lack of lymphadenopathy or blood involvement, a CXR and/or ultrasound of peripheral nodal basins can be performed though may be of low yield. In more advanced stage patients, CT scan of the chest, abdomen, and pelvis +/- FDG-PET are recommended for further evaluation.

Lymph Node Evaluation:

Any lymph node that is 1.5 cm or greater in size, and/or is fixed, firm, or irregular would be considered suspicious for lymphoma and an excisional biopsy (preferred for staging) vs core biopsy would be of diagnostic value.

Once all the diagnostic data are obtained, comprehensive staging is possible. Since staging of the disease is constantly modified, please see the National Comprehensive Cancer Network ((NCCN) website (www.nccn.org/professionals/physician_gls/f_guidelines.asp) under guidelines for Non Hodgkins Lymphoma for the most up-to-date staging data.

• Diagnosis confirmation

In early-stage disease, the histopathologic diagnosis of MF may be very difficult, as it can appear similar to benign dermatoses such as psoriasis and chronic contact dermatitis or eczema. As a result, clinical correlation and repeated follow-up biopsies are crucial.

Differentiation of SS from non-neoplastic erythrodermas is at times very difficult. The differential includes atopic dermatitis, psoriasis, drug reactions and pityriasis rubra pilaris (PRP) among many others. Identification of a clonal T-cell population in the blood allows for differentiation of SS from other benign forms of erythroderma. Performing peripheral blood flow cytometry is critical as an expanded population of phenotypically abnormal T-cells can be found in more than 80% of patients with SS, whereas this finding is quite unusual in the other disorders.

It can be difficult to clinically differentiate between tumor stage MF and anaplastic large cell lymphoma (ALCL) as both can be CD30+. Typically, ALCL is associated with the new onset of a limited number of tumor nodules (often single lesions or several). It is also quite unusual for MF tumors to spontaneously regress whereas this can occur in a small percentage of cases of ALCL.

Accurate diagnosis is important given the risk of disease progression of CTCL when immunosuppressive medications are used for a presumed different diagnosis.

Who is at Risk for Developing this Disease?

Mycosis fungoides (MF) is the most common type of CTCL. It generally presents in older adults (median age 55-60), however it may also occur in children and adolescents and has a male predominance. It has an Incidence rate of 6.4-9.6/1,000,000 persons. While the incidence is increasing, it is unclear how much of that increase is due to more accurate diagnosis.

MF accounts for approximately 1% of all non-Hodgkin’s lymphomas. SS accounts for about 10% of cases of CTCL. A subset of patients diagnosed with LyP have an increased risk of developing a secondary lymphoproliferative disorder including MF.

What is the Cause of the Disease?

• Etiology

The exact etiology of MF/SS remains unknown though it is thought that chronic antigenic stimulation may lead to uncontrolled clonal expansion of T-cell helper memory cells in the skin. Some patients may have a genetic predisposition: there are rare cases of familial occurrence. An environmental factor is not necessarily thought to play a role, given that the development of MF in unrelated married individuals is rare. However, in view of the rising incidence and cluster areas of occurrence, environmental factors should be sought. Immunosuppression may also predispose patients to developing CTCL.

The role of cytomegalovirus (CMV), Epstein-Barr virus (EBV), HHV-8 and Borrelia burgdorferi have been suggested, but not confirmed. HTLV-1/2, the cause of adult T-cell leukemia/lymphoma, produces a clinical condition that mimics mycosis fungoides and Sezary syndrome. HTLV-1/2 are endemic in southern Japan, the Caribbean islands, and part of the Middle East. In rare patients, the same T-cell clone has been detected in those who have second lymphomas questioning a common origin of disease.

• Pathophysiology

Skin-homing: MF cells express cutaneous lymphocyte antigen (CLA), the ligand for E-selectin, which is expressed on endothelial cells in the setting of an inflammatory process. Skin associated chemokines such as CC-chemokine ligands 17 and 22 help facilitate skin-trafficking.

Epidermotropic: The chemokine receptor CCR4 is increased on MF cells. CCL 17, produced in the epidermis, is a critical ligand for CCR4 leading to recruitment of cells into the epidermis.

Increased Th2 environment: The malignant CD4+ T-cells produce Th2 cytokines. This results in decreased Th1 helper T-cell function, reduced delayed-type hypersensitivity, elevated IgE and eosinophilia, with increased levels of IL-4 and IL-5. Activated T-cells also produce IL-10, IL-13 and TGF-beta which can inhibit cell-mediated immunity. In SS, the transcription factors important for a Th2 environment such as GATA-3 and JUNB are overexpressed. Patients also have a defect in Th1 cytokine production with decreased levels of IL-12, IFN-alpha, and IFN-gamma. IL-13 may serve as an autocrine and paracine growth factor for the malignant T-cells.

Activated malignant T-cells: They express several activation markers including CD45RO, proliferating-cell nuclear antigen, and CD25. They fail to express CD40L upon engagement of the TCR resulting in a reduction of dendritic cell (DC) activation and cytokine production.

Clonal dominance: Chromosomal rearrangment hotspots have been detected that may allow for a clonal population to emerge (deletions on 1p, 17p, 10q, and 19 and gains at 4q, 18, and 17q).

Defective apoptosis: Early patch and plaque stage MF lesions, as well as circulating malignant T-cells may show defects in Fas expression or constitutive STAT 3 or 5 activation. Tumors have been shown to have p-53 expression defects, microsatellite instability, and p16/p15 alterations. Amplification of JUNB has been noted which plays a role in T-cell proliferation, differentiation and apoptosis.

Decreased normal lymphocyte populations: As the disease progresses, the levels of cytotoxic CD8+ T-cells, CD56+ NK cells, and myeloid and plasmacytoid dendritic cells decrease. In addition, it is thought that MF/SS patients have a reduction in their T-cell receptor repertoire/complexity.

Molecular changes: Patients with CTCL may have distinct microRNA changes allowing them to be differentiated from benign dermatoses with >90% accuracy (miRNAs 155. 203, 205, 326, 663, and 711). Programmed death 1 (PD1) is expressed on neoplastic cells in Sezary syndrome and may decrease with appropriate treatment.

In summary, Sezary syndrome is characterized by certain immunologic findings. There are increased levels of CD4+/CCR4+/CD26- T-cells. There is a systemic increase in IL-4, IL-5 and IL-10 levels, which leads to an increase in peripheral eosinophilia and elevated IgE levels. Sezary syndrome is also associated with a decrease in CD8+ T-cells, dendritic cells, and CD56+NK cells. A decrease in systemic levels of IL-12, IFN-alpha, and INF-gamma leads to a decrease in cell mediated cytotoxicity.

Systemic Implications and Complications

• Extracutaneous Disease

The most frequent sites of extracutaneous involvement are the lymph nodes, lung, spleen, and liver. Other than focal involvement in advanced disease, the bone marrow is usually spared. SS may be associated with involvement of any organ, including the central nervous system (CNS). Microscopic involvement may occur early, prior to overt disease. Thus, CNS and other organ involvement may be subtle at its earliest involvement. Please refer to patient management section for appropriate work-up of extracutaneous disease.

• Complications

Since these patients can have extensive breakdown of their skin, they are at higher risk for infection. In addition, they may be immune deficient due to both their disease and medications. As a result, septicemia and/or pneumonia are common causes of death. Patients with erythroderma are often carriers of Staphylococcus aureus with a high rate of infection with MRSA.

In SS, involvement of the bone marrow, other than focally, is rare in early stages, but may be found in later stages.

Patients with MF/SS are at increased risk of developing a secondary malignancy including non-melanoma skin cancers, melanoma, colonic carcinoma and second lymphoproliferative disorders. Because of the endogenous immune suppression associated with SS, these patients may be at greater risk for more rapid dissemination of a second malignancy.

• Associated Systemic Disorders

MF can be associated with other hematologic disorders such as lymphomatoid papulosis (LyP), CD30+ anaplastic large cell lymphoma (ALCL), and Hodgkins Lymphoma and other B-cell lymphomas. Their onset may or may not coincide with the diagnosis of MF or SS. Rarely, the same clone may be identified in MF and an associated T-cell lymphoproliferative process.

• Prognosis

Patients with limited T1 stage have a life expectancy similar to that of the general population.

All patients with MF/SS have a risk of disease progression (RDP) of 34%. The risk increases with advancing stage of disease. For example, patients with stage IIIA disease without peripheral Sezary cells (B0a) have a lower risk of disease progression than those with stage IIIB disease with peripheral blood involvement (B1).

Predictors of reduced survival and increased RDP:

• Advanced skin (T) stage: the presence of plaques has a worse prognosis than patches (T2b vs T2a); those with thick plaques have a worse prognosis than those with thin

• Overall clinical stage: patients with N1 nodes have poorer survival in comparison to those with N0; patients with stage Nx have a greater relative risk of death stressing the importance of lymph node biopsies for those with palpable or radiologically enlarged nodes

• Increased age

• Male sex

• Level of peripheral blood tumor burden

• Presence of a T-cell clone in the peripheral blood in patients with B0 disease

• Increased lactate dehydrogenase (LDH)

• Folliculotropic MF: these patients may have a resistance to skin-directed therapy or a differing underlying biology

• Large cell transformation: has more significance for disease progression

• Beta-2-microglobulin levels

Predictors of improved survival and decreased RDP:

• Hypopigmented MF

• MF with LyP

• Poiklodermatous MF

• Earlier stage, particularly IA

• In the setting of a malignant CD4 phenotype, many CD8+ T-cells in the cutaneous infiltrate

Treatment Options

Treatment options are summarized in Table I, Table II, and Table III.

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