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Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides

Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides
Authors:
Richard T Hoppe, MD
Youn H Kim, MD
Section Editors:
Timothy M Kuzel, MD, FACP
John A Zic, MD
Deputy Editors:
Alan G Rosmarin, MD
Rosamaria Corona, MD, DSc
Literature review current through: Oct 2022. | This topic last updated: Sep 23, 2022.

INTRODUCTION — Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T cell lymphoma (CTCL).

MF is a mature T cell non-Hodgkin lymphoma with presentation in the skin but with potential involvement of the nodes, blood, and viscera. Skin lesions include patches or plaques that may be localized or widespread, tumors, and erythroderma.

SS is defined as a distinctive erythrodermic CTCL with a leukemic involvement of malignant T cells clonally matching that in the skin.

This group of disorders differs from other primary CTCLs by virtue of unique clinical features and histopathology. This topic review will discuss the clinical features, diagnosis, and staging of MF. The diagnosis of SS and the management of these disorders are discussed separately.

(See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

(See "Treatment of Sézary syndrome".)

(See "Treatment of early stage (IA to IIA) mycosis fungoides".)

(See "Treatment of advanced stage (IIB to IV) mycosis fungoides".)

PATHOGENESIS — The cause of MF is unclear, but T cell receptor (TCR)/T cell activation, altered JAK-STAT signaling, RNA splicing abnormalities, and epigenetic alterations are common features.

Current hypotheses include genetic and epigenetic abnormalities [1-6]. Although environmental and occupational exposure to solvents and chemicals has been implicated in the etiology of the disease, a large case-controlled study failed to support this hypothesis [7]. An infectious etiology for MF has been suggested, but no relation has been confirmed [8]. Human T-lymphotropic virus type I (HTLV-I) has been reported in the peripheral blood or cutaneous lesions of some patients with MF [9,10]. However, an equal number of studies have evidence against a role of HTLV-I [11,12].

Genetics — A heterogeneous spectrum of genetic abnormalities have been identified in CTCL cells, mostly deletions and translocations that involve different chromosomes or chromosomal segments [13-17]. One report identified dozens of driver mutations, including some that are predicted to affect chromatin; immune surveillance; RNA splicing; and signaling through MAPK, NFkB, PI3K, and T cell receptor [17]. Gene expression profiles and microRNA profiling suggest that MF and Sézary syndrome (SS) may be separate entities with differing pathogenesis [18-21]. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome", section on 'Pathophysiology'.)

Whole-exome sequencing analysis on samples from MF and SS found that, compared with normal controls, the tumor-suppressors MLL3 (KMT2C) and TP53 were the most frequently mutated genes [16]. Point mutations and copy number gains of TNFRSF1B (which encodes tumor necrosis factor receptor 2 [TNFR2]), which is expressed in mature T cells and regulates signaling pathways related to T cell survival and proliferation, were also found with high frequency [16].

Rearrangements in multiple genes involved in signal transduction and transcriptional regulation have been found in tumor-stage MF by whole-genome and RNA-sequencing [22]. Deletion of CDKN2A, as well as the tumor suppressor genes HNRNPK, encoding a nuclear ribonucleoprotein implicated in the pathogenesis of acute myeloid leukemia, and SOCS1, encoding a direct inhibitor of JAK kinase activity, were the most frequent genetic alterations.

Immunopathogenesis — The neoplastic cells in MF and SS are thought to derive from skin tropic memory CD4+ T cells [23]. Based on the studies demonstrating different T cell molecular profiles in MF and SS, it has been hypothesized that MF and SS originate from distinct memory T cell subsets [19]. Malignant T cells from MF skin express the CCR4+/CLA+/CCR7–/L-selectin– immunophenotype of the skin resident memory T cells (TRM). In contrast, clonal malignant T cells from the blood of SS patients express the CCR4+/CCR7+/L-selectin+ phenotype of the skin-tropic central memory T cell (TCM) [19]. The expression of surface ligand CCR4 determines the T cell skin homing ability, while CCR7/L-selectin determine their ability to re-circulate between blood and lymph node.

The tumor microenvironment plays a role in the pathogenesis and progression of MF and SS. While in early stage MF, the T cell infiltrate is composed of both malignant CD4+ and reactive CD8+ T cells, with a dominant Th1 cytokine pattern; in advanced lesions and in Sezary syndrome, there is gradual increase in CD4+ T cells and a switch to a Th2-dominated microenvironment [24]. This suggests a loss of CD8-mediated immunity and anti-tumor response with disease progression. The increased production Th2 cytokines interleukin (IL)-4, IL-5, and IL-13 is concurrent with a decrease in the expression of Th1 factors such as T cell-specific T-box transcription factor (T-bet), interferon gamma (IFN-γ), Stat4, and IL-12 [25-28].

EPIDEMIOLOGY — The incidence of MF in Europe and the United States is approximately six cases per million per year, accounting for about 4 percent of all cases of non-Hodgkin lymphoma [29-31]. Surveillance, Epidemiology, and End Results (SEER) registry data suggest that the age-adjusted incidence of MF increased from 1973 to 1998 [29]. The reasons for this are unclear but might be due to improvements in detection, changes in the classification of this disease, or an increase in the underlying etiologic agent(s). Since 1998, the SEER registry reported incidence appears to have stabilized [31].

The peak age at presentation is 55 to 60 years, with a 2:1 male:female ratio [30,32,33]. The disease is more common in Black populations [34-37]. Although MF is a disease mainly of older patients, it can be seen in patients under the age of 35 years with similar clinical findings and course [38-40].

MF is not a genetically inherited disease. Siblings and children of patients with MF do not have a substantially increased risk of developing MF. While there has been a single report of familial clustering of MF in Israel, no other cases of familial MF or Sézary syndrome have been reported by this or other groups [41]. Evaluation with whole genome sequencing and studies to rule out HTLV1-associated adult T cell leukemia/lymphoma are necessary to confirm whether familial or hereditary MF exists.

CLINICAL FEATURES — Patients with MF commonly present with persistent and/or slowly progressive skin lesions of varying size and shape. Skin lesions may be localized or widespread patches or plaques, tumors, and/or generalized erythroderma. The skin is often pruritic and the patient's quality of life can be profoundly affected [42]. Other clinical manifestations include opportunistic infections, alopecia, and, less commonly, involvement of other organs. Some of these clinical features are used in the point-based diagnostic algorithm. (See 'Diagnosis' below.)

Premycotic period — A definitive diagnosis of MF is often preceded by a "premycotic" period ranging from months to decades, during which the patient may have pruritus and nonspecific, slightly scaling skin lesions and nondiagnostic biopsies for months to years [43]. These lesions may wax and wane over years, and a diagnosis of parapsoriasis en plaque or nonspecific dermatitis is often made (picture 1) [44].

Some patients with these nonspecific dermatoses, even those with demonstrated T cell clones [45], may never progress to have a definitive diagnosis of MF; their skin eruptions may resolve without any specific treatment or occasionally after simple treatment with topical corticosteroids [46]. Repeated biopsies must be obtained in patients suspected of having MF, even when an initial biopsy is negative.

In the past, occasional patients presented with what was thought to be de novo tumors, so-called tumor d'emblee. However, with advances in immunophenotyping, most of these cases would now be classified as other cutaneous T cell lymphomas or B cell lymphomas of the skin.

Signs and symptoms

Skin lesions — MF is characterized by heterogeneous cutaneous manifestations including patches, plaques, tumors, generalized erythroderma, alopecia, or rarely, papules. Although any body surface may be affected (even palms and soles), in limited presentations of disease lesions are often confined to the bathing trunk distribution [47,48]. Patches or plaques will be limited to <10 percent of the skin surface in approximately 30 percent of patients, while more generalized patch/plaque involvement is seen in approximately 35 percent [49]. Tumors and erythroderma will be present in approximately 20 and 15 percent, respectively.

Patches, plaques, and tumors – The most common initial skin lesions are scaly patches or plaques, which can be pruritic. While most patch lesions are large (greater than 5 cm in diameter), they often vary in size, shape, and color (picture 2A-C) [47]. As the disease progresses, patches may evolve into infiltrated plaques with a more generalized distribution (picture 3A-B), and patients with a history of plaque disease may develop ulcerated or exophytic tumors (picture 4A-B). A tumor is defined as a dome-shaped solid skin lesion >1 cm in diameter. However, most patients with initial patch or plaque disease who are treated never progress to have more advanced cutaneous disease [50].

Papules – Keratosis pilaris-like lesions represent inflamed follicular-based papules or scale that may signal follicular involvement with or without mucinosis (picture 5) [51,52].

Hypopigmented or hyperpigmented lesions (picture 6) – Poikiloderma is the presence of mottled pigmentation, epidermal atrophy, and telangiectasia associated with slight infiltration (picture 7) [53]. Hypopigmented lesions are relatively uncommon and mostly seen in children and in patients with darker skin [54]. These lesions may occur with or without more typical MF lesions. Rarely, the hypopigmented lesions may have an annular appearance [55].

Generalized erythroderma – Generalized erythroderma (picture 8) typically represents more advanced disease and may be accompanied by either atrophic or lichenified skin, and plaques or tumors [43]. These patients are almost always intensely symptomatic from pruritus and scaling, and often have lymphadenopathy due to diffuse and severe skin involvement. Generalized erythroderma is more commonly observed in those with Sézary syndrome, where it is required to make the diagnosis. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

Alopecia – Alopecia is common and can present as reduced hair density diffusely over the scalp and body or as patches of alopecia. Patients with MF can present with varying degrees of alopecia (picture 9). A retrospective analysis of 1550 patients with MF and/or Sézary syndrome found that 38 patients had patchy, total-scalp, or universal alopecia [56]. Patchy alopecia was clinically indistinguishable from alopecia areata in 34 percent. The majority of remaining cases presented with alopecia in discrete patch/plaque or follicular lesions. Total-body hair loss was seen in five patients with generalized erythroderma and Sézary syndrome. Alopecia may not be reversible, even with effective treatment for the disease.

Erosions and superinfection – Patients are often colonized with Staphylococcus aureus, and erosions and superinfection from constant scratching are common. (See 'Infections' below.)

Less common or rare clinical variants demonstrate:

Bullous/vesicular lesions – Flaccid or tense blisters (which may have a positive Nikolsky sign) occurring on normal skin, on an erythematous base, or within typical plaques and tumors of MF.  

Purpuric lesions – As the name implies, the pigmented purpura-like variant of MF presents with persistent, pigmented purpuric lesions.

Dry scaling – The ichthyosiform variant can present clinically as dry scaling of the trunk and extremities similar to that seen in ichthyosis.

Acral lesions – Involvement of body protrusions such as the elbows, knees, buttocks, toes, heels, lips, and ears.

Leonine facies – Thickened and redundant skin of the face and scalp giving a lion-like appearance.

Pruritus — Pruritus is one of the most common and the most debilitating symptoms of patients with MF [42,57]. In a retrospective analysis of bedside surveys from 486 patients with MF (85 percent) or Sézary syndrome (15 percent), pruritus was reported by 66 percent of patients [58]. Using a visual analog scale of 1 to 10 to measure severity, the mean pruritus rating was 4.2 for all patients. The severity rating increased with increasing disease stage, being 3.4, 6.6, and 7.7 in patients with early stage (IA to IIA) disease, late stage (IIB to IVB) disease, and Sézary syndrome, respectively. It is not necessarily related to the degree of blood involvement or the extent and depth of erythema, and it can be associated with sleep dysfunction, anxiety, and depression.

Extracutaneous disease — The likelihood of developing extracutaneous disease, exclusive of peripheral blood involvement, correlates with the extent of skin involvement. Extracutaneous disease, other than lymph node involvement, is rare among patients with limited patch or plaque disease, relatively uncommon among those with generalized plaque (8 percent), and most likely among patients with tumors or generalized erythroderma (30 to 42 percent) [43]. Thus, extracutaneous disease is more commonly observed among those with Sézary syndrome. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'Disease stage'.)

Extracutaneous manifestations include involvement of regional lymph nodes (approximately 30 percent in MF [59]), lungs [60], spleen, liver, and gastrointestinal tract. Bone marrow involvement is rare [61-63]. Autopsy studies and a large case series have shown that involvement of any organ, including the central nervous system, can occur in the advanced stages of the disease [64,65]. (See "Clinical presentation and diagnosis of secondary central nervous system lymphoma", section on 'Incidence and risk factors'.)

Associated conditions

Infections — Patients with MF are at increased risk for infection due to a combination of immune dysfunction and physical factors [66]. Patients with MF demonstrate impaired cellular and humoral immunity [66]. They have an increase in the severity of viral (eg, herpes) and bacterial infections [67]. In one study, the majority of patients with MF demonstrated colonization with Staphylococcus aureus in the skin or nares [68]. Colonized patients treated with antibiotics to eradicate the bacteria often demonstrate clinical improvement of signs of skin involvement with the lymphoma. There have also been reports of progressive multifocal leukoencephalopathy due to polyomavirus in patients with MF in the absence of immunosuppressive therapy [69].

Second malignancies — Both the SEER (Surveillance, Epidemiology, and End Results Program) United States population-based and university referral center registries have demonstrated an increased incidence of second cancers, specifically other lymphomas, in patients with MF or Sézary syndrome [70-72].

PATHOLOGY — MF was first described by the French dermatologist Alibert in 1806, with the mushroom-like appearance of the cutaneous tumor nodules giving the disease its name. Clinical-pathologic correlation is key to the diagnosis. (See 'Diagnostic algorithm' below.)

Morphology

Skin biopsy — Skin biopsies in MF demonstrate small to medium-sized atypical mononuclear cells with cerebriform nuclei infiltrating the upper dermis, especially at the dermal-epidermal junction, and epidermal keratinocytes (epidermotropism) or forming intraepidermal aggregates (Pautrier microabscesses) (picture 10). Pautrier microabscesses are pathognomonic, yet uncommon (picture 11) [61-63]. Spongiosis, or the collection of fluid in the epidermis, is not seen.

In a retrospective review of histology specimens from 64 patients with MF confirmed by clinical course and immunophenotyping results and 47 patients who were biopsied to exclude MF and did not have the disease, the following parameters were found to be significant discriminators between MF and non-MF on univariate analysis [46]:

Pautrier's abscesses (present in 38 percent of cases of MF)

Haloed lymphocytes

Exocytosis

Disproportionate epidermotropism

Epidermal lymphocytes larger than dermal lymphocytes

Hyperconvoluted intraepidermal lymphocytes

Lymphocytes aligned within the basal layer

Of these findings, haloed lymphocytes (intraepidermal lymphocytes with vacuoles around them (picture 12)) were the most robust discriminator of MF from non-MF on multivariate analysis. Based on the severity of the epidermal and dermal involvement, the categories "diagnostic of," "consistent with," and "suggestive of" MF are often used. In practice, only those skin biopsies labeled as "diagnostic of" or "consistent with" MF have established the diagnosis.

Several histologic variants of MF are recognized, some of which have prognostic importance:

Folliculotropic MF is a variant of MF that often lacks evidence of epidermotropism and is characterized by atypical CD4+ T lymphocytes that surround and permeate the hair follicles (folliculotropism) with or without associated follicular mucinosis [73,74]. Data regarding the prognosis of patients with folliculotropic MF are difficult to ascertain because of the differential impact in early versus advanced stage disease. This is discussed in more detail separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'Folliculotropic variant'.)

Patients with plaque-type or erythrodermic MF may develop cutaneous tumors with large cell histology (large cell transformation), a feature that may be associated with a worse prognosis. By definition, such large cells are at least four times greater in size than a small lymphocyte. The transformation to large cell histology is diagnosed when more than 25 percent of the total lymphoid infiltrate is made up of these large cells or if these cells create microscopic nodules [63,75,76]. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome", section on 'Transformation to large-cell histology (LCT)'.)

A granulomatous reaction may be seen on histology with one of many patterns: sarcoidal pattern, granuloma annulare-like pattern (also known as interstitial mycosis fungoides), and granulomatous pattern with multinucleated giant cells.

Lymph node biopsy — Patients with MF and extensive skin involvement may have enlarged lymph nodes demonstrating histologic findings of dermatopathic lymphadenitis, showing sinus histiocytosis, an abundance of pigment-laden macrophages, and a small number of atypical lymphocytes. The degree of lymph node replacement by these atypical cells can be described as a grade that has prognostic significance [77]. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

The detection of abnormal cells in the lymph node is facilitated by the use of Southern blot or polymerase chain reaction (PCR) analysis. Potential neoplastic involvement with clonal TCR rearrangement may be demonstrated even in lymph nodes that show only dermatopathic changes in routine evaluation [78]. However, the clinical implication of lymph node involvement that is detectable only at the molecular level is unclear, and usually is not associated with as severe an impact on prognosis as when involvement is detected by routine light microscopy.

Circulating Sézary cells — Sézary cells are mononuclear cells with a cerebriform nucleus (picture 13 and picture 14). These cells can be observed in small numbers among healthy individuals [73]. In those with MF, an increased number of Sézary cells may be seen in the peripheral blood. An absolute count ≥1000 Sézary cells/mm3 or ≥1000/microL CD4+CD26– or CD4+CD7– cells by flow cytometry is a diagnostic criterion for Sézary syndrome (table 1). (See 'Diagnosis' below and "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

Immunophenotyping — Immunophenotyping is used to support or confirm results of the routine histology [79,80]. Determining the immunophenotype can be technically difficult. Sensitivity and specificity vary depending on the type of tissue used (frozen section versus paraffin block), antibody used, and cutoff value selected. In routine practice, expression of CD2, CD3, CD5, and CD7 are key factors in determining the immunophenotype while other markers are still under investigation. (See 'Diagnosis' below.)

Immunophenotyping can help distinguish MF and Sézary syndrome from reactive or inflammatory lymphoid infiltrates in the skin that display markers of mature lymphocytes. Mature T cell markers include CD2, CD3, CD5, and CD7. Lack of one or more of these markers indicates a more immature cell and is strongly suggestive of lymphoma [81]. MF typically expresses CD2, CD3, CD4, and CD5 and lacks expression of CD7 and CD8; rare subtypes include expression of CD8 (but not CD4) or expression of T cell receptor (TCR) gamma/delta (but not TCR alpha/beta) [63].

A decrease in the expression of these markers can also be determined by evaluating the epidermal/dermal discordance. Discordance is found when the antigen is deficient among the cells restricted to the epidermis but is present in the cells in the dermis. An epidermal/dermal discordance for CD2, CD3, CD5, and CD7 suggests the diagnosis of a T cell lymphoma but is limited in its ability to subclassify it as MF.

Expression of CD30 is present in 40 to 50 percent of histologically transformed MF [82]. Some expression of CD30 is common in all patients with MF, not limited to those with histologic large cell transformation; in a study of 47 cases of MF, at least rare dermal CD30-positive cells were seen in all cases [83]. The percentage of dermal CD30-positive cells increased with increasing disease stage and was an independent predictor of adverse outcomes.

T cell receptor (TCR) gene rearrangement — TCR gene rearrangements can be detected using PCR amplification or next generation sequencing [84-87]. The gene rearrangement tests are utilized primarily when the histology and immunophenotyping results are equivocal in patients whose clinical presentation is strongly suggestive of MF, and may be less valuable when used to determine prognosis. This is of particular importance in patients with erythroderma since morphology is often non-diagnostic in this patient group. Examination of multiple biopsies from the same patient taken simultaneously or consecutively from two anatomically distinct skin sites usually, but not always, demonstrates the same TCR gene rearrangement [88,89].

The presence of TCR rearrangement among T cell clones is not diagnostic of MF. Instead, the presence of such abnormalities is only one component of a possible diagnosis. As an example, there are non-malignant disorders in which T cell clonality is observed:

Some non-malignant or pre-malignant cutaneous conditions may be accompanied by evidence of an expanded T cell clone [45,90].

Innocent cytotoxic T cell clones are occasionally detected in the peripheral blood of elderly patients [91].

DIAGNOSIS

Evaluation — The diagnosis of MF is suspected in patients who present with chronic nonspecific dermatitis, poikilodermatous skin findings, or generalized erythroderma. Skin biopsy with routine histology is the single most important laboratory tool that will assist the clinician in establishing the diagnosis of MF [92]. Often, multiple skin biopsies are required. If only one biopsy is performed, it should include the lesional skin with the most induration. With the exception of emollients, all topical treatments should be avoided for two to four weeks prior to biopsy since they may interfere with the interpretation of the biopsy specimen [47]. A minimum of a 4 mm punch biopsy is recommended. In most cases, biopsies can be placed in formalin prior to hematoxylin and eosin staining and any additional pathology tests. Patients from endemic regions (eg, Japan and the Caribbean) should have serologic testing for HTLV-I.

An algorithm for diagnosing and staging early MF, based on clinical, histopathologic, molecular, and immunopathologic criteria, has been proposed by the International Society for Cutaneous Lymphoma (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC) [47,73]. It is recommended that all patients enrolled in trials or databases for MF should have their diagnosis confirmed by the ISCL/EORTC algorithm as described below. Diagnostic, staging, and treatment guidelines for MF are also available from the National Comprehensive Cancer Network (NCCN) [93].

Diagnostic algorithm — The diagnosis of MF can be made using the point-based algorithm created by the ISCL/EORTC, which incorporates clinical, histopathologic, molecular, and immunopathologic criteria (table 2). Points are scored for clinical, histopathologic, molecular biological, and immunopathologic categories [47,73]. A diagnosis of MF is made when a total of four points or more is determined:

Clinical criteria: Patient has persistent and/or progressive patches and plaques plus (two points given if two of the following are present, one point is given if one of the following is present): lesions in a non-sun-exposed location, size/shape variation of lesions, poikiloderma. (See 'Skin lesions' above.)

Histopathologic criteria: Superficial lymphoid infiltrate present plus (two points are given if both of the following are present, one point is given if only one of the following is present): epidermotropism without spongiosis, lymphoid atypia.

Molecular biological criteria: If clonal TCR gene rearrangement is present, give one point.

Immunopathologic criteria: Give one point if any of the following is present: less than 50 percent of the T cells express CD2, CD3, or CD5; less than 10 percent of the T cells express CD7; there is discordance of the epidermal and dermal cells with regard to expression of CD2, CD3, CD5, or CD7.

DIFFERENTIAL DIAGNOSIS — MF typically presents as an indolent cutaneous eruption with erythematous scaly patches or plaques, often resembling common skin disorders such as eczema, psoriasis, parapsoriasis, photodermatitis, or drug reactions. The cutaneous tumors seen in patients with MF can also resemble those tumors seen with other cutaneous lymphomas. The ISCL/EORTC diagnostic algorithm described above aims to use clinical, histopathologic, molecular biological, and immunopathologic features to help make these diagnostic decisions easier. (See 'Diagnosis' above.)

Other causes of erythroderma — Erythroderma is a less common cutaneous presentation of MF and is seen most commonly in patients with generalized atopic dermatitis, contact dermatitis, drug eruptions, or erythrodermic psoriasis. It can also be seen in patients with the idiopathic hypereosinophilic syndrome, some of whom have abnormal T cell clones [94]. The approach to patients with generalized erythroderma is presented separately. (See "Erythroderma in adults".)

Other causes of pruritus — Pruritus is a frequent manifestation of MF, although it is typically not present in the absence of cutaneous findings [95]. The erythrodermic form of MF and Sézary syndrome are extremely pruritic and there are case reports of pruritus preceding the onset of skin findings by several years [96]. Pruritus is a common symptom that occurs in a diverse range of skin diseases and may appear as a prominent feature of extracutaneous disorders such as systemic, neurologic, and psychiatric diseases (table 3). The evaluation of the patient with pruritus is discussed separately. (See "Pruritus: Etiology and patient evaluation".)

Sézary syndrome — As described above, patients with MF may have atypical lymphocytes with cerebriform nuclei (ie, Sézary cells) in their peripheral blood (picture 13). A diagnosis of Sézary syndrome is made when there is a particularly high number of these cells circulating in the peripheral blood in the presence of a cutaneous erythroderma occupying more than 80 percent of the body surface area. This is equivalent to the T4 and B2 designation in the TNMB classification system (table 1). The diagnosis of Sézary syndrome is presented in more detail separately. (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

Adult T cell leukemia-lymphoma — Adult T cell leukemia-lymphoma (ATL) is a peripheral T cell lymphoma associated with infection by the human T-lymphotropic virus, type I (HTLV-I). Approximately 50 percent of patients with ATL will have skin lesions at diagnosis, often simulating those seen in MF. ATL, however, is much more likely to have disseminated extracutaneous disease with frequent lymphoma in the nodes, liver, bone, and central nervous system. A key differentiating feature is the presence of HTLV-I in the malignant cells of ATL, which can be determined by testing for the antibody in the blood. ATL is common in Japan and the Caribbean and is unusual in the mainland United States. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)

Subcutaneous panniculitis-like T cell lymphoma — Subcutaneous panniculitis-like T cell lymphoma (SPTCL) is an uncommon peripheral T cell lymphoma that typically presents with one or more usually painless subcutaneous nodules or poorly circumscribed indurated plaques that may clinically resemble panniculitis. Similar to MF, SPTCL expresses CD3, does not express CD56 or demonstrate Epstein-Barr virus infection, and has clonally rearranged T cell receptor (TCR) genes. SPTCL differs from MF in that it is centered on the subcutaneous tissue rather than the dermis and epidermis, does not express CD4, and expresses CD8 and cytotoxic granule proteins (TIA-1, granzyme B, and/or perforin). Patients with symptoms and signs of hemophagocytic lymphohistiocytosis (HLH) often have a less favorable outcome [97]. (See "Clinical manifestations, pathologic features, and diagnosis of subcutaneous panniculitis-like T cell lymphoma".)

Primary cutaneous anaplastic large cell lymphoma — Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) is a peripheral T cell lymphoma characterized by the diffuse infiltration of the upper and deep dermis and the subcutaneous tissue by large lymphoid cells. Unlike MF, PC-ALCL expresses cytotoxic molecules (TIA-1, granzyme B, and/or perforin) and CD30. (See "Primary cutaneous anaplastic large cell lymphoma".)

Cutaneous gamma/delta T cell lymphoma — Cutaneous gamma/delta T cell lymphoma (G/D TCL) is another cytotoxic T cell lymphoma that can present with HLH, thus it is important to consider evaluation for HLH whenever clinically indicated [98]. G/D TCL is usually an aggressive type of cutaneous T cell lymphoma [63,99]; however, a subset of patients can present indolently with patches and plaques that mimic clinical and pathologic features of MF. These patients can later develop the more typical features of the aggressive G/D TCL.

Cutaneous B cell lymphoma — The skin lesions of CTCL may not be easily distinguished clinically from those of B cell lymphomas. MF can be distinguished from cutaneous B cell lymphomas through their expression of T cell markers such as CD2, CD3, and CD5. In addition, MF can be identified by TCR gene rearrangement studies. The diagnosis of primary cutaneous B cell lymphomas is presented separately. (See "Primary cutaneous follicle center lymphoma" and "Primary cutaneous marginal zone lymphoma" and "Primary cutaneous large B cell lymphoma, leg type".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary cutaneous lymphoma".)

SUMMARY

Description – Mycosis fungoides (MF) is an indolent extranodal non-Hodgkin lymphoma (NHL) of T cell origin characterized by skin involvement.

Epidemiology – MF is an uncommon disorder that accounts for approximately 4 percent of NHL. The peak incidence of presentation is in individuals >55 years and it is more common in males and Black patients. (See 'Epidemiology' above.)

Pathogenesis – The cause of MF is uncertain. Heterogeneous genetic abnormalities have been described, including deletions and translocations of various chromosomes and numerous molecular abnormalities (eg, involving genes associated with chromatin maintenance, immune surveillance, RNA splicing, intracellular signaling). (See 'Pathogenesis' above.)

Presentation – Most patients present with pruritic skin changes that may precede recognition and diagnosis for months to years. Cutaneous manifestations are variable and include patches, plaques, tumors, generalized erythroderma, poikiloderma, or rarely, papules. Extracutaneous manifestations, while uncommon, include involvement of regional lymph nodes, lungs, spleen, liver, gastrointestinal tract, and bone marrow. (See 'Clinical features' above.)

Sézary syndrome is diagnosed when circulating abnormal T cells (Sézary cells) are ≥1000 /microL (table 1). (See "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

Pathology – Skin biopsies demonstrate mononuclear cells with cerebriform nuclei infiltrating the upper dermis (epidermotropism) or forming intraepidermal aggregates (Pautrier microabscesses). Immunophenotype and T cell receptor (TCR) gene rearrangement studies can support or confirm results of the routine histology in patients whose clinical presentation is strongly suggestive of MF. (See 'Pathology' above.)

Folliculotropic MF is a distinct entity that is characterized by atypical lymphocytes that surround and permeate the hair follicles (folliculotropism).

Diagnosis and staging – MF should be suspected in patients with chronic nonspecific dermatitis, poikilodermatous skin findings, or generalized erythroderma.

Diagnosis – MF is diagnosed according to clinical, histopathologic, molecular, and immunopathologic criteria established by the ISCL/EORTC (International Society for Cutaneous Lymphoma [ISCL] and European Organization of Research and Treatment of Cancer [EORTC]) consensus scoring system (table 2). (See 'Diagnosis' above.)

Staging – Staging is according to ISCL/EORTC criteria, as described separately. (See "Staging and prognosis of mycosis fungoides and Sézary syndrome".)

Differential diagnosis – The differential diagnosis of MF includes common skin disorders, such as eczema or psoriasis, and other cutaneous lymphomas. (See 'Differential diagnosis' above.)

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Topic 1674 Version 34.0

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