Cutaneous T-Cell Lymphoma: Mycosis Fungoides and Sézary Syndrome

Cutaneous T-Cell Lymphoma: Mycosis Fungoides and Sézary Syndrome

John A. Zic

Jeff P. Zwerner

Laura Y. McGirt

Claudio A. Mosse

John P. Greer

Cutaneous lymphomas are a heterogeneous group of non-Hodgkin lymphomas (NHLs) of T- and B-cell origin in which the skin is the primary organ of involvement. Primary cutaneous lymphomas usually present without signs of extracutaneous malignancy at onset of symptoms; they represent an entity distinct from nodal lymphomas with secondary cutaneous involvement. In 1975, Lutzner, Edelson, and associates introduced the term cutaneous T-cell lymphoma (CTCL) to describe the spectrum of skin-based lymphomas of T-cell origin including classical mycosis fungoides (MF) and Sézary syndrome (SS).1, 2 This chapter is a review of the history, epidemiology, clinicopathologic features, and therapy of these lymphomas.


The incidence of the primary CTCLs has risen dramatically and consistently since 1973.82 Based on data from the Surveillance, Epidemiology, and End Results (SEER) Program of nine cancer registries, the incidence of CTCL in the United States increased from 2.8 to 6.3 to 9.6 cases per 1 million population in the periods 1973 to 1977, 1988 to 1992, and 1998 to 2002, respectively.82 During the period 1973 to 2002, the overall annual age-adjusted incidence of CTCL for the original nine SEER registries was 6.4 per million persons, representing 4% of all reported NHLs.82 Bradford et al. reported an age-adjusted CTCL incidence of 7.7 per million persons from 2004 to 2005.83 Because the number of patients with early-stage MF often is not reported to tumor registries, the actual incidence may be higher. In one study, missed
cases were estimated to constitute 17% of MF.84 Thus, using the most recent incidence rate, the incidence of new cases of CTCL in the United States in the first decade of the 21st century is almost 3,000 cases per year. The incidence of MF increases with advancing age, and the median age is usually between 60 and 70 years, with an incidence rate of 24.6 per million for persons 70 to 79 years of age and a peak around 80 years of age.82,83 It is rare in patients <30 years of age. However, in the 1990s there emerged several reports of children and adolescents affected with MF and SS.85, 86, 87 One study found that 4% to 5% of patients with MF had onset of their eruption before 20 years of age,87 whereas the more recent epidemiologic study by Criscione and Weinstock showed only 1% of cases of CTCL to be in the <20 years age group.82 A study from the International Childhood Registry of Cutaneous Lymphoma found the mean age of onset and diagnosis of pediatric cutaneous lymphoma to be 7.5 years (±3.8 years) and 9.9 years (±3.4 years), respectively.88

Blacks are more likely to develop MF compared to whites, 9.0 to 10.0 versus 6.1 to 8.1 per million incidence rates, with the greatest racial differences seen among the younger patient populations.82, 83 Both Asian/Pacific Islanders and Hispanic whites have an incidence rate of 5.1 per million.83 Men are significantly more likely to develop CTCL than women, with an age-adjusted incidence rate almost twice that of women.82, 83 The epidemiologic study by Criscione and Weinstock found the incidence rates of CTCL to be correlated with high physician density, high family income, high percentage of population with a bachelor’s degree or higher, and high home values, suggesting that increased detection of CTCL may play a role in the increased incidence rates since 1973.82

The etiology of MF/SS remains unknown, but genetic, environmental, and infectious agents have been implicated as possible factors in triggering lymphocyte activation and/or lymphocyte transformation.89, 90 A recent study found that not only did the antioxidative effects of wine consumption fail to protect against the development of MF, but patients who consume >24 g of alcohol per day demonstrated a higher incidence of MF than matched controls (adjusted odds ratio 3.02, 95% confidence interval 1.34 to 6.79).91 Also significant was that the alcohol effect remained constant regardless of beverage type.

Rare familial clusters of CTCL cases have been reported,92 and an increased incidence has been noted in patients with certain histocompatibility antigens.93, 94 A rare case of transformed CTCL developing in a husband and wife suggested a common environmental or infectious exposure in the etiology of their disease.95 Early reports implicated an increased risk of developing CTCL in people employed in a manufacturing occupation, particularly those related to petrochemicals, textiles, or metals, or in farming, with exposure to pesticides or herbicides.96 However, two case-control studies have failed to confirm these observations.97, 98 Results of other studies have suggested that patients with MF have increased contact allergies, but Whittemore et al. were unable to substantiate the association in a case-control clinical study.98

Human retroviruses have been suggested as possible etiologic agents in CTCL. HTLV-I was described initially in a CTCL patient who had an aggressive clinical course; however, this disease was later identified as adult T-cell leukemia/lymphoma (ATL), which is endemic to Japan, the Caribbean, and other areas of the world but can have cutaneous lesions similar to CTCL (see ATL in Chapter 88).99 Serologic findings for HTLV-I/II in patients with CTCL are negative in the vast majority of patients.100, 101, 102 In support of the association of HTLV-I/II and MF, virus particles indistinguishable from HTLV-I have been identified using electron microscopy on immortalized MF cells,103 and combined PCR/Southern blot analyses have demonstrated HTLV pol, tax, and/or rex sequences in PBMC lysate extracts and lesional skin from patients with MF/SS.100, 104, 105, 106 Further support of a potential HTLV-1/CTCL association was suggested after inoculation of immunosuppressed rats with PBMC extracts from patients with MF/SS. A novel anti-HTLV-I antibody was detected in the serum of 29% of the animals, whereas PBMC from healthy controls did not elicit an anti-HTLV-1 antibody response. These findings lend further support to the role of HTLV-1 as being at least a co-factor in the pathogenesis of CTCL.107 Based on these studies, some authors contend that the strongest evidence of an etiologic/pathogenic factor for CTCL relates to the presence of a defective or variant HTLV-I virus.70, 104 Other authorities,101, 102, 108, 109 however, disagree, citing seven series that found no proviral HTLV-I sequences in 332 CTCL patients101, 110, 111, 112, 113, 114, 115 and four studies that detected the proviral sequences in 10% of 176 patients.116, 117, 118, 119 Future development of advanced molecular techniques should eliminate the difficulty of establishing with certainty the presence or absence of HTLV-I proviral sequences in patients with CTCL.108, 120 More recently, there have been studies evaluating the presence of HHV-8 and the Merkel cell polyoma virus, but neither of these infectious agents has been significantly identified.121, 122 A separate group evaluated MF skin samples for the presence of multiple infectious agents (HTLV, Epstein-Barr virus, and Borrelia burgdorferi) and found that 21/83 MF samples had two or more infectious agents identified as compared to 1/83 healthy controls.123


MF usually evolves over a long period, so patients often have a long premycotic or pre-malignant phase with eczematous skin eruptions between 4 and 10 years before a histologic diagnosis is established.70 The differential diagnosis during this period includes chronic eczematous, atopic or contact dermatitis, which may evolve slowly into eruptions clinically suggestive of parapsoriasis en plaque, poikiloderma atrophicans vasculare, or other benign papulosquamous skin diseases.124 Failure of the lesions to respond to standard topical therapy may be an early clue of a different diagnosis. However, initial lesions occasionally appear to improve following topical steroid application, which masks early recognition of the underlying malignancy.125 Because of the difficulty in diagnosis in the premycotic phase of MF, careful follow-up with serial skin biopsies is warranted in patients with suspect lesions (see section “Diagnostic Evaluation”).

The earliest diagnostic phase of MF is the patch phase, characterized by persistent scaly macules and patches that vary in size, shape, and color, tend to involve sun-protected sites, and are occasionally associated with pruritus (Fig. 92.4A).5, 124, 126 Early MF patches and plaques, unlike other eczematous eruptions, are usually asymptomatic. Other, less common early skin findings in MF include poikiloderma,127 hypopigmentation,128 hyperpigmentation (Fig. 92.4B), alopecia, pruritus alone,129, 130, 131 and porokeratosis-like lesions.132 Recently, several cases of “invisible MF” were described. Afflicted patients presented only with persistent, generalized pruritus and no clinical eruption.129, 130, 131 Random biopsies of “normal” skin confirmed the diagnosis of MF.

Plaques are sharply demarcated, scaly, elevated lesions that may have annular, arcuate, or serpiginous borders (Fig. 92.4C). Plaques with thick scale can mimic psoriasis or nummular eczema, whereas annular lesions with central clearing may be confused with tinea corporis.124 Ultraviolet radiation occasionally induces regression of patches and plaques, further delaying correct diagnosis. Prominent involvement of the palms and/or soles may result in hyperkeratosis, fissuring, or frank keratoderma (Fig. 92.4D).133

The tumor phase is heralded by the onset of dome-shaped, deep red to violaceous nodules emerging in areas of uninvolved skin or in pre-existing plaques.124 The tumors may ulcerate and become secondarily infected (Fig. 92.4E), and there is a predilection for the body folds and face, where dermal
thickening, coalescing plaques, and tumors may result in characteristic “leonine facies” (Fig. 92.4F). The tumor stage is more clinically aggressive than the patch and plaque stages, and may be associated with histologic transformation to a large cell process with a vertical growth phase (see section “Histopathology and Prognosis”).124 Rarely, patients with MF will present initially with tumors without the preceding patch and plaque phases (the MF d’emblée variant).6, 134 It is very common for more advanced patients to have patches, plaques, and/or tumors present simultaneously on different areas of their skin.70

FIGURE 92.4. The cutaneous phases of mycosis fungoides. A: Early patch-stage lesions in a sun-protected region. B: Hyperpigmented diffuse patches on the back of a dark-skinned patient. C: Scattered thin and thick plaques on the back. D: Early keratoderma of the sole. E: Ulcerated tumor within a plaque on the posterior leg. F: Coalescing nodules and tumors with dermal thickening forming “leonine facies” in this patient with transformed cutaneous T-cell lymphoma (CTCL). See text for full description.

Generalized erythroderma may develop as the initial presenting sign of MF/SS or may accompany plaques and tumors.70 In SS, the leukemic variant of CTCL, erythroderma, and circulating tumor cells (Sézary cells) in the peripheral blood may be accompanied by generalized lymphadenopathy, splenomegaly, keratoderma, vitiligo-like hypopigmented patches,135 alopecia,
ectropion, nail dystrophy, and ankle edema.136 Intense pruritus and cutaneous pain are common in SS, and when the palms and soles are affected with scaling and fissuring, walking and manual dexterity become difficult.136


The term cutaneous T-cell lymphoma or CTCL is a general term that encompasses a variety of diseases, including MF and SS. In addition, there are other cutaneous T-cell lymphoproliferative disorders that appear to be specific entities with unique clinical, histologic, and prognostic features. In an effort to recognize the separate disease processes, a new classification of primary cutaneous lymphomas was formulated jointly by the World Health Organization (WHO) and the European Organisation for Research and Treatment of Cancer (EORTC) in 2005 (Table 92.1).137 The most recent WHO classification of tumors of hematopoietic and lymphoid tissues presented in 2008 essentially mirrors, with a few exceptions, the 2005 WHO-EORTC classification scheme.138, 139 MF is the most common subtype, accounting for almost 50% of all CTCL, and this term should be used only for patients with the classic presentation of patches and plaques with slow progression as described by Alibert and Bazin.137 The WHO-EORTC classification recognizes three variants of MF and the T-cell lymphoproliferative disorder lymphomatoid papulosis (LyP) as a distinct subtype of CTCL for the first time. The following sections focus on the histopathology and immunopathology of MF, SS, and the other types of primary CTCLs.


Cutaneous T-cell Lymphomas

Mycosis fungoidesa

Variants of MF:

Folliculotropic mycosis fungoidesa

Pagetoid reticulosisa

Subtype of MF:

Granulomatous slack skina

Sézary syndromeb

CD30+ lymphoproliferative disorders of the skin

Lymphomatoid papulosisa

Primary cutaneous anaplastic large-cell lymphomaa

Subcutaneous panniculitis-like T-cell lymphomaa

Primary cutaneous T-cell lymphoma, unspecifiedc

Provisional entities:

Primary cutaneous epidermotropic CD8+ T-cell lymphoma (provisional)b

Cutaneous γδ-positive T-cell lymphoma (provisional)b

Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphomaa

Extranodal NK-/T-cell lymphoma, nasal typeb,d

Adult T-cell leukemia/lymphomad

Cutaneous B-cell Lymphomas

Primary cutaneous marginal zone B-cell lymphoma (MALT-type)a

Primary cutaneous follicle center lymphomaa

Follicular, follicular and diffuse, diffuse growth patterns

Primary cutaneous diffuse large B-cell lymphoma, leg typee

Primary cutaneous diffuse large B-cell lymphoma, othere

Intravascular large B-cell lymphomad,e

Precursor Hematologic Neoplasm

Blastic plasmacytoid dendritic cell neoplasm (previously CD4+/CD56+ hematodermic neoplasm)

EORTC, European Organization for Research and Treatment of Cancer; MALT, mucosal associated lymphoid tissue; MF, mycosis fungoides; NK, natural killer WHO, World Health Organization.

a Indolent (5-year disease-specific survival >75%).

b Aggressive (5-year disease-specific survival <25%) clinical behavior.

c Aggressive (5-year disease-specific survival <25%) clinical behavior (excluding provisional entities).

d Typically, an extracutaneous lymphoma with skin as a secondary site.

e Intermediate (5-year disease-specific survival 25% to 75%).

Modified from Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-3785.


Tissue Handling

Skin biopsies for diagnosis of MF/SS must be properly handled to maximize the diagnostic information obtained. These studies include routine histology, immunophenotyping, and molecular genotyping. Communication between the clinical staff, dermatologists, and pathologists is essential to ensure that the appropriate types of biopsies are done and are properly handled. In general, 6-mm punch biopsies are recommended. Multiple biopsies from different skin lesions may be necessary to establish a definitive diagnosis of MF/SS, particularly in early-patch-stage lesions. Topical steroids may blunt many of the histologic features of MF/SS and should be discontinued for 2 to 3 weeks prior to biopsy. A careful drug history should be taken prior to biopsy, because certain drug eruptions can closely mimic early MF, particularly phenytoin and other anticonvulsants.140 Although advancements in immunohistochemical protocols and molecular diagnostics allow most studies to be performed on formalin-fixed tissue, optimally skin biopsies for possible CTCL should be sent to the pathology or dermatopathology lab fresh, on saline-soaked gauze or in tissue culture media such as RPMI. These biopsies can then be divided for the various diagnostic studies. Punch biopsies can be divided into halves, one half for routine histology and the other half for immunophenotyping and/or molecular diagnostic studies. Sections for routine histology should be fixed in a good nuclear fixative such as B5 to facilitate evaluation of nuclear morphology and recognition of characteristic cerebriform cells. If it is a large biopsy of a cutaneous tumor or a lymph node biopsy, it may provide adequate tissue to prepare cell suspensions for immunophenotyping by flow cytometry and for cytogenetic studies. The tissue for immunophenotyping by flow cytometry should be promptly delivered to the appropriate laboratory in cell culture media. Tissue for molecular studies should be snap-frozen in liquid nitrogen and stored at -70°C. For leukemic infiltrates, cytochemical stains can be performed on air-dried touch imprints from freshly cut surfaces. A small sliver of the biopsy can be shaved off and fixed in glutaraldehyde for electron microscopy if needed. Lymph nodes should be worked up as previously described.141


Cutaneous Features of Mycosis Fungoides/Sézary Syndrome

In general, the histologic diagnosis of MF/SS in skin biopsies is based on criteria similar to those used for the diagnosis of other lymphoid neoplasms, including the presence of an infiltrative or destructive growth pattern and cytologic atypia. The distribution of the infiltrate within the skin biopsy is also important (Fig. 92.5A). The characteristic atypical lymphocytes in MF and SS are dysplastic cerebriform T-cells with enlarged hyperchromatic nuclei and complex nuclear folding. Demonstration of cerebriform nuclear
folding requires good fixation (such as B5 fixation), thin (4-µm) sections, and examination under 100× oil immersion. Others have used special methods such as 1-µm sections of plastic-embedded tissue, electron microscopy, or nuclear morphometry.142 Diagnostic criteria for cutaneous involvement by MF are best illustrated in plaque-stage lesions (Fig. 92.5B,C). The essential criteria for diagnosis are (a) a bandlike lymphocytic infiltrate in the superficial papillary dermis, (b) epidermotropism, and (c) atypical cerebriform T-cells in the dermal and epidermal infiltrates.143, 144 Pautrier microabscesses (Fig. 92.5D) are characteristic of MF but are often absent in patch-stage lesions, erythroderma, and nonepidermotropic tumors. Diagnosing early-patch-stage lesions is often difficult. In a morphologic study of >700 early-patch-stage lesions by Massone et al., the histologic features most helpful for diagnosing MF were (a) epidermotropism, particularly with a basilar lymphocytosis (23%) or with “haloed” lymphocytes (40%); (b) a dermal lymphocytic infiltrate that is bandlike (30%) or patchy lichenoid (66%); and (c) interface dermatitis (59%).145 Large convoluted lymphocytes in the epidermis were found only in 9% of cases, and Pautrier microabscesses were found in 19%. The authors noted that although these cytologic changes are highly specific, the architectural abnormalities (infiltrate, epidermotropism) were more sensitive in diagnosing MF, as has also been suggested by others.146 Earlier studies have shown similar criteria as being valuable in diagnosing MF “haloed” epidermotropic cerebriform T-cells along the basal layer of the epidermis, disproportionate epidermotropism (intraepidermal lymphocytes without accompanying spongiosis), and medium to large cerebriform cells in the epidermis and clustered in the dermis.143, 147, 148 Several studies have pointed to the association of papillary dermal fibrosis with MF/SS; however, at least one study found that in a carefully selected population of early, untreated MF patients this finding argued against a lymphoma diagnosis.149

FIGURE 92.5. A: Mycosis fungoides (MF), patch stage. A bandlike lymphocytic infiltrate occupies the superficial papillary dermis with single-cell epidermotropism by atypical, “haloed” cerebriform T-cells, preferentially involving the basal layer (hematoxylin and eosin, ×50). B: MF, plaque stage. A bandlike lymphocytic infiltrate occupies the papillary dermis with epidermotropism by atypical cerebriform T-cells, focally forming small Pautrier microabscesses (hematoxylin and eosin, ×25). C: MF, thick plaque. A dense bandlike lymphocytic infiltrate fills the papillary dermis and extends into the reticular dermis. Prominent epidermotropism by atypical, enlarged cerebriform T-cells creates large Pautrier microabscesses (hematoxylin and eosin, ×25). D: MF, Pautrier microabscess. High magnification of a Pautrier microabscess shows characteristic small to medium cerebriform T-cells with highly convoluted nuclear folding. The Pautrier microabscess recapitulates normal interactions between components of the skin-associated lymphoid tissue, i.e., cutaneous T-cells, Langerhans histiocytes (2 cells with large pale nuclei in the center), and keratinocytes (hematoxylin and eosin, ×500).

Spongiosis should be minimal in relationship to epidermotropism in MF and SS. Biopsies with prominent spongiosis must be differentiated from eczematous or spongiotic dermatitis. Microvesiculaion and Langerhans cell microabscesses are rarely present in MF/SS and would point toward a spongiotic process. Eosinophils and plasma cells are often present in early patch- and plaque-stage MF, and represent a nonspecific reactive component.

It is important to understand that a definitive diagnosis of MF may not be possible in some early-patch-stage lesions. Multiple biopsies of separate skin lesions, immunophenotyping, and TCR gene rearrangement studies may help confirm the diagnosis in difficult cases. Even these ancillary studies may be inconclusive in early lesions. The reported range of sensitivity of T-cell clonality detection is large, with some studies reporting as few as 20% of early-patch-stage lesions being clonal150 to as many as 71%.151 Likely, this variability reflects variability in density of infiltrate in early lesions, variability in source material for DNA extraction (frozen vs. paraffin), and variability of the clonality assay [Southern blot vs. PCR vs. denaturing gel electrophoresis vs. capillary electrophoresis]. In later plaque- and tumor-stage lesions, T-cell clonality can typically be detected in >90% of cases.151, 152 Recently, a PCR-based clonality protocol has been proposed and validated (BIOMED-2) in an attempt to provide some degree of standardization.77, 153 In addition, several techniques have been advocated, such as comparing clonality studies from disparate clinical lesions and using complementary clonality studies (TCR β and TCR γ) that may increase the specificity and sensitivity of the molecular studies.154, 155 Despite these advancements, however, a lack of demonstrated clonality in a histologically or clinically suspicious lesion should not prevent a diagnosis of CTCL. Likewise, the presence of a clonal population does not equate with malignancy as many benign dermatoses may demonstrate clonality.156

Tumor-stage MF is characterized histologically by a dense dermal infiltrate involving the papillary and reticular dermis, often with extension into the subcutis. In contrast to patch- and plaque-stage lesions, MF tumors are often nonepidermotropic and may spare the dermal—epidermal interface. Furthermore, the malignant T-cells in tumor-stage MF often display various degrees of histologic transformation, with medium and large pleomorphic cells, immunoblastic large cells, and anaplastic large cells.157, 158 The diagnosis of malignancy in the tumor stage is rarely in question, but recognition of MF origin for tumors with large-cell transformation may be obscured by their resemblance to other NHLs. A careful search for dysplastic cerebriform T-cells and residual foci of epidermal infiltration near the edges of tumors often provides histologic evidence of MF origin in difficult cases.157 Previous or concurrent biopsies of earlier-stage MF lesions may also help confirm the diagnosis in these cases.

Generalized exfoliative erythroderma is characteristic of SS but may also occur in MF.159 Cutaneous biopsies of erythroderma in MF/SS often lack many of the hallmark features found in patch/plaque MF, such as epidermotropism and lymphocytes aligned along the basement membrane.160 In fact, in one study, up to 17% of skin biopsies of patients with established SS were considered nondiagnostic because of insufficient epidermotropism.161 Evaluation of the peripheral blood for circulating tumor cells and/or molecular analysis of the skin and peripheral blood for a clonal rearrangement of the TCR may help establish the diagnosis of MF/SS in cases for which skin biopsies are histologically suspicious, but nondiagnostic. In addition, the finding of identical clonal populations in the skin and peripheral blood is very supportive of a lymphoma diagnosis.162

Large-cell Transformation of Mycosis Fungoides/Sézary Syndrome

Approximately 20% of low-grade MF and SS undergo secondary transformation to high-grade large-cell lymphoma with a predominance (>25%) of large transformed lymphocytes (Fig. 92.6).157 Secondary large-cell transformation of MF/SS may resemble immunoblastic large-cell lymphoma, pleomorphic large-cell lymphoma, or ALCL.157, 163 It has been shown that secondary large-cell lymphoma is immunophenotypically and clonally related to earlier MF/SS biopsies taken prior to transformation.164 Cutaneous large-cell transformation usually occurs late in tumor-stage lesions, but it can occasionally be seen in plaques or erythrodermic MF and may be present in the initial diagnostic biopsy (mycosis d’emblée variant). Lymph nodes are the most common site of extracutaneous large-cell transformation, but it may also occur in other extracutaneous sites. Approximately 50% of secondarily transformed large-cell lymphomas express CD30.165 In MF patients with large-cell transformation the absence of CD30 expression has been associated with a reduced disease-specific survival.166 It is important to distinguish secondary large-cell transformation of MF/SS from unrelated primary cutaneous large-cell lymphoma, LyP, and secondary cutaneous involvement by systemic large-cell lymphoma because of prognostic differences.167 This is particularly true for secondary CD30+ large-cell lymphoma resulting from transformation of MF/SS, which has a poor prognosis, in contrast to primary cutaneous CD30+ ALCL and LyP, both of which have a favorable prognosis.168, 169 Differentiating these entities is often impossible on histologic grounds alone and requires close collaboration between the clinician and pathologist to establish the correct diagnosis in the WHO-EORTC classification scheme.

FIGURE 92.6. Large-cell transformation of mycosis fungoides (MF). This represents secondary transformation of low-grade MF to high-grade immunoblastic large-cell lymphoma. This tumor is composed of sheets of large transformed cells or immunoblasts with round to oval nuclei, dispersed chromatin, and prominent nucleoli. Several mitoses are present (hematoxylin and eosin, ×500).

Extracutaneous Mycosis Fungoides/Sézary Syndrome

Extracutaneous dissemination is generally considered to be a late occurrence in MF/SS because the disease is clinically limited to the skin for prolonged periods of time in most patients. Using more sensitive techniques such as cytogenetics, electron microscopy, and immunophenotypic studies, extracutaneous disease has been found in nearly 90% of MF/SS patients at initial staging in one case series.170 There is evidence that nodal involvement as detected with highly sensitive molecular techniques can segregate otherwise low-stage patients into high-risk and low-risk groups;171 however, assessment of regional lymph nodes is not standard practice in early-stage MF patients. Although autopsy studies have histologically documented widespread extracutaneous disease in most patients,172 most series were performed several decades ago, when detection of early disease was difficult.

Extracutaneous MF/SS has histologic features that are usually similar to those seen in the skin. Dysplastic cerebriform T-cells are the most helpful diagnostic feature for recognition as extracutaneous disease. Almost every organ has been involved by MF/SS in autopsy series, but the most frequent sites are the lymph
nodes, liver, spleen, and lungs, which may be involved in >50% of more advanced cases.172 Other common sites include kidney, bone marrow, thyroid, heart, pancreas, gastrointestinal tract, and central nervous system. Lymph nodes represent the most frequent site of extracutaneous disease in pathologic staging studies; up to 50% of lymph nodes are positive by light microscopy at initial staging.173 Several series from the 1980s found visceral involvement present in ˜15% of initial staging liver and bone marrow biopsies.157, 173, 174 When staging laparotomies were routinely performed in the past, ˜30% of spleens were microscopically involved by MF/SS.175 Extracutaneous CTCL, particularly visceral disease, is strongly associated with advanced-stage skin disease (tumors and erythroderma) and SS.174 Because tumor-stage MF and generalized erythroderma are frequently nonepidermotropic, it has been suggested that loss of epidermotropism may play an important role in systemic dissemination.

Lymph Node Pathology

With up to 50% of staging lymph node biopsies being microscopically involved by MF/SS, lymph nodes are the earliest and most common site of extracutaneous dissemination.173 Nevertheless, the ISCL guidelines only recommend excision of lymph nodes if they are either >1.5 cm in greatest transverse diameter or are palpably irregular, firm, or fixed lymph nodes regardless of size.176 Partially effaced nodes often have an interfollicular pattern with preservation of reactive follicular centers, but eventually most lymph nodes become completely effaced. As lymph nodes become progressively infiltrated, the cerebriform T-cells tend to become larger and more pleomorphic, with increased numbers of large transformed cells.177 Over 35% of positive nodes will show complete large-cell transformation with pleomorphic, immunoblastic, or anaplastic large-cell morphology.157, 177, 178 In contrast to MF, lymph nodes from patients with SS tend to be effaced by more monomorphic infiltrates of small to medium cerebriform T-cells,179 but may also undergo large-cell transformation in some cases.157, 165

Bone Marrow Involvement

The bone marrow in MF and SS is generally thought to be spared until late in the course of the disease, including in patients with large numbers of circulating Sézary cells.70, 170 Early studies suggested that antemortem marrow involvement occurred in <3% of MF/SS patients,170 yet the marrow was involved in nearly 50% of patients at autopsy in several series from the 1970s.172, 180 Marrow involvement typically manifests as nonparatrabecular lymphoid aggregates with cerebriform lymphocytes. Molecular studies have shown that in patients with a defined clonal T-cell rearrangement in the skin, approximately 20% will have an identical T-cell clone detected in their blood or bone marrow. Moreover, all patients with bone marrow involvement by molecular studies had blood involvement as well, but only 76% of patients with blood involvement had bone marrow involvement.181 Sibaud et al. were unable to demonstrate that bone marrow involvement was associated with a worse prognosis in a multivariate analysis of their data; however, blood involvement was an independent variable for disease progression. In patients with SS, subtle small interstitial clusters of Sézary cells have been identified in up to 90% of cases, suggesting that most patients with circulating Sézary cells have early systemic dissemination of disease.174 Detection of these subtle interstitial infiltrates of Sézary cells requires careful examination under oil immersion (100×) to identify the cells with abnormal cerebriform nuclear folds. Identification can be facilitated with immunoperoxidase studies for T-cell markers such as CD3, CD4, and CD7. Flow cytometry using a broad array of T-cell markers including CD3, CD4, CD8, CD7, and CD26 is also useful for detecting marrow involvement.

Other Extracutaneous Sites

Splenic and hepatic involvement by MF and SS is common and can be staged using imaging criteria rather than by invasive methods.182 Liver involvement in initial staging procedures has been found in 8% to 16% of cases.173 Disseminated MF and SS tend to form nodular infiltrates of atypical cerebriform T-cells within the portal tracts or hepatic lobules. Cerebriform T-cells within the hepatic sinusoids without formation of focal aggregates are not considered diagnostic of liver involvement in the presence of peripheral blood involvement. Splenic infiltration was documented in 31% of staging laparotomies in one series.175 The atypical cerebriform T-cells usually infiltrate the red pulp diffusely, but they may home to the periarteriolar lymphocyte sheath.180 Splenic rupture has been reported in a rare case with massive splenic involvement by CTCL.183

All other suspected sites of visceral involvement should be confirmed by biopsy if possible. Antemortem pulmonary manifestations of MF and SS are generally uncommon but may occasionally present clinically as interstitial or nodular pulmonary infiltrates.184 However, the lungs are frequently involved by MF/SS at autopsy.172 Infiltrates of atypical cerebriform T-cells usually spread along the alveolar septae with preservation of the alveolar architecture. In some cases, the infiltrates may also fill alveolar spaces.

Blood Involvement

The ISCL has defined three stages of blood involvement for MF/SS.176 Patients with B2 peripheral blood involvement have >1,000 Sézary cells/mm3, where the Sézary cells are distinguished by their large nuclear size (>15 µm) and high nuclear contour index (Fig. 92.7).185 In one study, increased large Sézary cells correlated significantly with poorer survival.186 However, size criteria alone would fail to recognize the small Sézary cell variant, which is similar in size to a normal resting lymphocyte. Because of the inherent difficulties in diagnosing peripheral blood involvement by MF/SS on peripheral smear review, additional technologies are now used including flow cytometry and molecular studies such as PCR. The ISCL considers a positive clonal TCR rearrangement in the blood coupled with either a CD4:CD8 ratio >10:1 or abnormal immunophenotype by flow cytometry (CD4+CD7 or CD4+CD26) as adequate evidence to constitute a positive peripheral blood for staging purposes.185 It has been shown that patients with B2 blood involvement have a statistically worse survival than those with B1 or B0 staging.186 ISCL B0 is defined as no increase in Sézary cells (<5% of peripheral blood lymphocytes). B0 cases with molecular detection of T-cell clonality (B0b) have a worse prognosis than
molecularly negative (B0a) cases even when the histologic criteria for blood involvement have not been met.162, 187, 188 In fact, T-cell clonality in the peripheral blood even in the absence of increased lymphocytes by morphology or flow cytometry (B0b) has been shown to convey a worse overall survival (OS), disease-specific survival and risk of disease progression.189 B1 stage is defined as the group of patients who fail to meet criteria for B2 or B1. These patients have >5% atypical T-cells but do not otherwise reach the criteria for B2 involvement. These patients can also be split into B1a molecular clone negative and B1b molecular clone positive cases. Although T-cell clonality is required for diagnosis of B2 stage, the presence of molecularly defined T-cell clones in elderly patients or in patients with other lymphoproliferative disorders is not uncommon151, 190, 191 requiring therefore correlation with the clonality of the cutaneous infiltrate or association with MF-associated immunophenotypic abnormalities (increased CD4:CD8 ratio, loss of CD7 or CD26 on CD4 T cells).

FIGURE 92.7. Sézary syndrome. The peripheral blood shows lymphocytosis. Most lymphocytes are Sézary cells with enlarged, highly convoluted nuclei and scant cytoplasm (hematoxylin and eosin, ×250).

Immunophenotyping Studies

T-cell origin of the neoplastic cells in MF and SS is well established as a memory T-cell that expresses CLA, the cutaneous lymphoid antigen homing receptor.192 The vast majority are derived from T-helper cells that express CD4 and other T-cell-associated antigens including CD2, CD3, CD5, CD45RO, and αβ TCRs (Fig. 92.8).193 However, a small number of CD8+ CTCL194 have been reported as well as γδ CTCL.195, 196 Of note, clinical presentation and behavior are crucial in distinguishing the CD8+ MF variant from the more aggressive primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma described in the updated WHO-EORTC nomenclature as a provisional subtype of peripheral CTCL. Furthermore, it is likely that most γδ CTCL would be classified as cutaneous γδ T-cell lymphoma (CGDTCL) in the WHO-EORTC scheme.137, 194, 197 Activation-associated (HLA-DR, CD25, CD30, CD38) and proliferation-associated (CD71, Ki-67) antigens are also frequently expressed in MF/SS, particularly in advanced stages.157

Aberrant T-antigen expression is often seen in MF and SS, particularly advanced plaque- or tumor-stage lesions, and can be used to help differentiate reactive dermatitis from MF/SS.198 Often, flow cytometry is used to assess antigen expression on the T-cells present in circulation or directly from involved skin biopsies. Aberrant T-cell phenotypes are defined as diminished or absent expression of pan-T-cell antigens (CD2, CD3, or CD5), absent T-subset antigen expression (CD4 CD8), or co-expression of T-subset antigens (CD4+ CD8+). Diminished or absent CD7 expression is one of the most common aberrant T-cell phenotypes in tissue sections of MF and SS.198 However, the isolated findings of loss of CD7 expression must be considered in the context of other clinical, histologic, and immunophenotypic findings in that expanded populations of CD7-negative T-cells can also be seen in benign dermatitides.193 More recently, several studies have shown that the loss of CD26 (dipeptidyl-aminopeptidase IV) expression is a characteristic feature of circulating Sézary cells that is likely more sensitive than loss of CD7 expression.199, 200, 201 Nevertheless, when considered as a group, loss of any major T-cell antigen (CD2, CD5, CD3, CD4, or CD7) is as or more sensitive a marker for SS and MF than loss of CD26.202

FIGURE 92.8. Frozen section immunohistochemistry of a cutaneous plaque in a patient with MF shows a marked predominance of CD4+ T-helper cells within Pautrier microabscesses and within the dermis. CD8 is essentially negative (Diaminobenzidinehematoxylin, ×50). MF, mycosis fungoides.

For histologic diagnosis of cutaneous lymphomas, immunohistochemistry can reliably differentiate among T-cell lymphomas, B-cell lymphomas, and Hodgkin disease. The most widely used paraffin-reactive T-cell antibodies include CD2, CD3, CD4, CD5, CD7, CD8, CD30, CD43, CD45RO, βF1, and TCR αβ. Although immunohistochemistry for CD7 can be helpful in evaluating early MF biopsies, loss of CD7 can be seen in a wide variety of reactive benign conditions requiring correlation with clinical, histologic, other immunophenotypic and molecular findings.203, 204 NK-cell or cytotoxic lymphocyte markers (CD56, granzyme B, perforin, and TIA-1) can be used as well if non-MF NK-/T-cell lymphomas are in the differential. CD20, CD79a, CD5, CD10, BCL-6, BCL-2, κ, λ, MUM1, and CD138 are the most widely used B-cell paraffin-reactive antibodies. When used in panels, these antibodies allow subclassification of most cutaneous lymphomas.

Oct 21, 2016 | Posted by in HEMATOLOGY | Comments Off on Cutaneous T-Cell Lymphoma: Mycosis Fungoides and Sézary Syndrome
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