Clinicopathological spectrum of mycosis fungoides

RE V I EW AR T ICLE

JEADV (2004) 18, 397 – 415 DOI: 10.1111/j.1468-3083.2004.00937.x

Clinicopathological spectrum of mycosis fungoides Blackwell Publishing, Ltd.

DV Kazakov, G Burg,† W Kempf * Sikl’s Department of Pathology, Charles University, Medical Faculty Hospital, Alej Svobody 80, Pilsen 304 60, Czech Republic †Department of Dermatology, Zurich University Hospital, Gloriastrasse 31, Zurich, CH 8091, Switzerland. *Corresponding author, tel. +41 1 225 2550; fax +41 1 255 4403; E-mail: [email protected]

ABSTRAC T Cutaneous lymphomas represent a heterogeneous group of T-, NK- and B-cell neoplasms, with mycosis fungoides (MF) being the most common subtype. MF has a plethora of clinicopathological manifestations. Many variants of this lymphoma differ substantially from the ‘classical’ Alibert–Bazin disease and are therefore sometimes referred to as ‘atypical’ forms of the disease. This review addresses the whole clinicopathological spectrum of mycosis fungoides with respect to epidemiology, clinical, histopathological, immunophenotypic and genotypic features and the clinical course and prognosis of its variants: classical, erythrodermic, follicular, syringotropic, bullous/vesicular, granulomatous, poikilodermic, hypo- and hyperpigmented, unilesional, palmoplantar, hyperkeratotic/verrucous, vegetating/papillomatous, ichthyosiform, pigmented purpuralike, pustular and mucosal involvement in MF. Key words: cutaneous lymphoma, mycosis fungoides, peripheral T-cell lymphoma Received: 14 January 2003, accepted 14 March 2003

Cutaneous lymphomas represent a heterogeneous group of T-, NK- and B-cell neoplasms, with mycosis fungoides (MF) being the most common subtype.1,2 MF is a peripheral non-Hodgkin T-cell lymphoma initially presenting in the skin. In the majority of cases, the disease evolves clinically through three stages – the patch, plaque and tumour stage. Histologically, the disease is typified by the proliferation of small cerebriform lymphocytes showing epidermotropism. Such clinicopathological presentation and course are usually regarded as ‘classical’ for this lymphoma.3 In fact, however, MF has a plethora of clinicopathological manifestations, some of which differ substantially from the classical Alibert–Bazin disease and are therefore sometimes referred to as ‘atypical’ forms of MF.4 This review addresses the clinicopathological spectrum of MF with respect to epidemiology, clinical, histopathological, immunophenotypical and genotypic features, clinical course and prognosis of its variants (Table 1).

‘Classical’ MF Men are more often affected than women (male : female ratio, 2 : 1). MF affects adults most frequently, usually in the fifth to sixth decade, although any age group may be involved.5 © 2004 European Academy of Dermatology and Venereology

fig. 1 The patch stage in classical mycosis fungoides: multiple scaling patches.

In some cases the disease starts with non-specific scaly lesions resembling various inflammatory dermatoses: chronic eczema, parapsoriasis, tinea corporis, atopic dermatitis, etc. (fig. 1). In other instances patients present with more distinctive irregular, well-circumscribed, scaly patches varying in size from 2–3 to 10–15 cm and more. The number of lesions is also variable. In some cases only a few patches can be observed, whereas in other instances the lesions can be numerous and widely distributed. Pruritus is common and often severe. In some cases the patches 397

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Table 1 Mycosis fungoides: clinicopathological spectrum ‘Classical’ Erythrodermic Follicular Syringotropic Bullous/vesicular Granulomatous Poikilodermic Hyperpigmented Hypopigmented Unilesional Palmoplanar Hyperkeratotic/verrucous Vegetating/papillomatous Ichthyosiform Pigmented purpura-like Pustular Extracutaneous

fig. 2 The plaque stage in classical mycosis fungoides: multiple, partially confluent thin and thick plaques.

show a tendency to partial spontaneous remission that, in combination with peripheral growth, leads to the development of lesions with unusual configurations (annular, semiannular, serpinginous, etc.). It usually takes several years until the patches progress into plaques and tumours, which may then ulcerate (figs 2 and 3). Lymph node and internal organs may become involved in the later stages of MF, which is usually associated with an aggressive clinical course.4,6– 10 A subset of patients has persistent patch-stage disease for many years or even decades. In very early stages (‘premycotic stage’) the histological picture is non-specific, characterized by a mild perivascular infiltrate in the upper dermis containing no atypical lymphocytes and lacking epidermotropism. Early MF can produce almost all of the patterns used for diagnosing inflammatory skin diseases.11 The histological findings become diagnostic in the late patch stage or the early plaque stage (‘thin plaque stage’), when a denser infiltrate is present, with lymphocytes lining up in the basal layer and showing single-cell epidermotropism (fig. 4).12,13 Most of the cells are small, well-differentiated lymphocytes with round or only slightly cerebriform nuclei. There may also be a mild acanthosis, hyperkeratosis, signs of basal layer

fig. 3 The tumour stage in classical mycosis fungoides: appearance of tumours in the background of pre-existing patches and plaques.

damage (pigment incontinence), oedema or fibrosis of the papillary dermis, and moderate proliferation of postcapillary venules. The infiltrate may contain an admixture of eosinophils, plasma cells, macrophages and dermal dendritic cells.11–14

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fig. 4 The patch stage in classical mycosis fungoides: scarce perivascular infiltrates in the upper dermis and lining-up of lymphocytes in the basal layer.

fig. 6 The plaque stage in classical mycosis fungoides: large Pautrier’s microabscesses.

fig. 5 The plaque stage in classical mycosis fungoides: a band-like infiltrate in the upper dermis with prominent epidermotropism. Marked acanthosis of the epidermis is seen.

The late plaque stage (‘thick plaque stage’) is typified by a dense, subepidermal, usually band-like infiltrate containing a higher number of cerebriform cells. Epidermotropism is more prominent with small intraepidermal clusters (2–3 cells) of lymphocytes (fig. 5). Large Pautrier’s microabscesses are seen only in a minority of cases (fig. 6). There may also be prominent collagen oedema, admixture of eosinophils and plasma cells.4,11–14 In the tumour stage, the infiltrate is nodular or diffuse and usually demonstrates loss of epidermotropism – a phenomenon assumed to result from loss of expression of some integrins, particularly αEβ7.15 In addition to a predominant population of small cerebriform cells there is a variable admixture of immunoblasts, lymphoblasts and medium-sized or large pleomorphic cells with hyperchromatic nuclei (fig. 7). In approximately 25% of cases, transformation into a high-grade lymphoma can

occur. In the transformed cases, the histological picture is identical to that seen in a correspondent primary cutaneous lymphoma arising without preceding MF. The morphological spectrum of the transformation is wide, with CD30-negative large-cell pleomorphic lymphoma being the most common type.16 The typical phenotype of the small cerebriform cells is CD2+, CD3+, CD5+, CD4+, CD45RO+, CD8–, CD25– (rarely CD25+), TCRβ+, CD30–.4,8,12 Scattered CD30+ small- to medium-sized cells found in the dermal infiltrate in some cases represent activated lymphocytes. As the disease progresses, an aberrant phenotype with loss of T-cell antigens (CD2, CD3, CD5) is a common finding.4 Aberrant expression of CD45RA, CD8 and TCRdelta by neoplastic lymphocytes may be detected in rare cases.17,18 The relationship between ‘cytotoxic MF’ and primary cutaneous CD8-positive epidermotropic cytotoxic T-cell lymphoma has not yet been settled. CD7 is expressed in one-third of the lesions. The dermal infiltrate contains admixed S-100+, CD1a+ interdigitating dendritic cells and Langerhans’ cells.4 Immunohistochemistry plays a minor role in the diagnosis of MF, as the neoplastic cells in early stages have no immunophenotypical aberrations.19 Functionally, the neoplastic lymphocytes in MF express a Thelper type 2 (TH2) phenotype, which accounts for many systemic changes associated with MF due to the production of a TH2-specific cytokine pattern [interleukin (IL)-4, IL-5, IL-10

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T-cell receptor (TCR)-beta- or gamma-chain genes are monoclonally rearranged in most cases, including patch-stage disease.22–24 Single-cell polymerase chain reaction (PCR) and molecular analysis of TCR genes after laser-beam microdissection have demonstrated that in early stages of MF a T-cell malignant clone is mainly confined to the epidermis.25,26 In later stages the clonal population is found only in the dermis.25 Even in early stages of MF, in addition to lesional skin, T-cell clones can be detected in lymph nodes and peripheral blood; the biological significance of this phenomenon remains unclear, as T-cell clones in the extracutaneous compartment are often different from those found in the skin and seem to represent an expanded normal T-cell population rather than circulating neoplastic cells.27 However, in advanced cases with extracutaneous involvement, the same clone is usually detected in the skin and in the extracutaneous lesions.28 Two (or more) unrelated clones are seen in the skin in about 20% of cases. In transformed cases the same clone is present in the pre-existing lesions and the high-grade lymphoma. The majority of MF patients show an indolent clinical course over years or decades.29 The prognosis of the disease is defined by its stage. Patients with early stages have an excellent prognosis with survival similar to that of an age-, sex- and racematched population.30,31 Factors indicating poor prognosis are advanced stage and age above 60 years. When extracutaneous involvement or transformation into high-grade lymphoma occurs, expected survival is usually less than 1 year.32

Erythrodermic MF and Sézary’s syndrome

fig. 7 (a) Loss of epidermotropism and extension of the infiltrate into the deep dermis. (b) The tumour stage in classical mycosis fungoides: appearance of medium-sized and large pleomorphic cells in the infiltrate.

and others] leading to eosinophilia, increase of immunoglobulin (Ig)E and IgA, and impaired delayed-type reactivity. This constellation of immune abnormalities is observed mainly in advanced stages of MF. In the early disease the production of IL-2 and interferon-γ (IFN-γ) by a predominant population of reactive TH1 cells inhibits the expansion of neoplastic TH2 lymphocytes.20,21

The topic of erythrodermic cutaneous T-cell lymphoma (CTCL) remains a matter of discussion. Sézary’s syndrome (SS) is referred to as an erythrodermic and leukaemic variant of CTCL. It is typified by infiltrative or exfoliative erythroderma involving more than 80% of the skin surface, enlargement of peripheral lymph nodes, and circulating atypical lymphoid cells (Sézary’s cells) of more than 5% of the total lymphocyte count in the peripheral blood.33 Other haematological criteria used for the definition of SS include the absolute number of Sézary’s cells per cubic millimetre (> 1000 cells/mm3) and the CD4/ CD8 ratio (10 or more).34,35 The skin is oedematous. Palmoplantar hyperkeratosis, hepatosplenomegaly, alopecia, ectropion and nail dystrophy are seen frequently.4,8 Erythroderma, lymphadenopathy and blood involvement in SS patients develop de novo within a short interval of time or may be preceded by pruritus or ‘non-specific’ dermatitis. By contrast, erythrodermic MF denotes a condition in which erythroderma occurs secondarily in patients with otherwise typical clinical features of MF. Some experts recommend using the term ‘SS preceded by MF’ for such cases.33 Patients with erythrodermic MF lack the blood findings typical for SS (erythrodermic MF: less than 5% circulating atypical cells) and often present with less prominent lymphadenopathy. Rarely do patients with otherwise classical

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fig. 8 Sézary’s syndrome: occurrence of numerous tumours denoting transformation into a high-grade lymphoma.

fig. 9 Follicular mycosis fungoides: follicular papules and cyst-like lesions in the reatroauricular area.

features of MF present with the blood findings typical of SS. According to the recent update on erythrodemic CTCL of the International Society for Cutaneous Lymphoma, such cases should be designated as ‘MF with leukaemic involvement’.33 The data on the latter condition are scarce. In general, SS and erythrodermic MF have histopathological and immunohistological features similar to classical MF.36 Some differences found in recent studies include more prominent parakeratosis and acantosis, less prominent epidermotropism, more significant papillary dermal fibrosis and teleangiectasias, and more mitotic figures in patients with erythrodermic MF/SS compared to the classical disease.37 SS is an aggressive disease with an overall survival rate at 5 years of between 11 and 20%.2,9 As in classical MF, transformation into a large-cell lymphoma may occur in the course of SS (fig. 8). In some cases of SS, the transformation occurs first in lymph nodes, whereas skin lesions may show improvement with treatment.38 Clinical behaviour and prognosis of erythrodermic MF are yet to be elucidated. The differential diagnosis of erythrodermic MF and SS includes adult T-cell leukaemia with erythroderma, and erythroderma associated with benign

inflammatory conditions such as psoriasis, atopic dermatitis, drug eruption, etc.

Follicular MF Follicular MF has been described in the literature under various designations, including folliculotropic MF, pilotropic MF, folliculocentric MF, MF-associated follicular mucinosis.39–50 Some authorities believe that the latter should be distinguished from follicular MF. However, we agree with others in that follicular MF and MF-associated follicular mucinosis belong to the spectrum of MF with a predilection for hair follicles.49 Patients with follicular MF demonstrate a significantly higher male : female ratio (4–5 : 1). Clinically, this type of the disease manifests itself as acneiform lesions, with formation of comedo-like plugs and epidermal cysts, follicular papules, follicular keratoses, erythematous patches and plaques, and hair loss in the affected areas (fig. 9). Some patients may develop mucinorrhoea (discharge of mucinous substance from follicular orifices). Face, neck and upper trunk are the sites of predilection.42,48,50 –53

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fig. 10 Follicular mycosis fungoides: a folliculocentric infiltrate and mucinous degeneration of the follicular epithelium. The epidermis is spared.

Histopathologically, follicular MF is typified by dense lymphocytic infiltrates surrounding and infiltrating the hair follicles and usually sparing interfollicular skin (fig. 10). The neoplastic lymphocytes are small- to medium-sized cells with irregular nuclei. In some cases, Pautrier’s microabscesses can be seen within the follicular epithelium. The follicles show cystic dilatation, cornified plugging and, in some cases, mucinous degeneration of the follicular epithelium, varying from focal spots of mucin deposition to complete destruction of follicle and mucin lakes.42,48,50–53 Infiltration of eccrine glands may be seen.51 A recent study of the Dutch lymphoma group has demonstrated that follicular MF shows more aggressive behaviour and a worse prognosis than classical MF.51 Akin to the classical disease, progression in follicular MF is associated with development of tumours or erythroderma. Comparison of the disease-specific and overall survival data demonstrated that patients with follicular MF have a comparable (at 5 years) or even worse (at 10 years) survival rate than patients with tumour-stage MF. The calculated risk of disease progression in patients with follicular MF also turned out to be higher than that in classical MF patients in the plaque and tumour stage. These findings raised the question of the usefulness of applying the standard clinical staging system for CTCL to patients with follicular MF, and the Dutch group proposed considering patients with follicular MF as having the tumour-stage disease, regardless of the clinical

appearance of the skin lesions. Because of the deep, peri- or intrafollicular location of the neoplastic infiltrate, patients with follicular MF may be less responsive to standard treatment modalities used for patients with classical MF.51 The exact cause of folliculotropism in follicular MF is not known. It has been suggested that certain changes in intercellular adhesion receptors may account for this phenomenon. In particular, the intercellular adhesion molecule-1 (ICAM-1) receptor has a high affinity for lymphocyte function-associated antigen-1 (LFA-1), which is expressed by high numbers of lymphocytes in MF. In one study, an increased expression of ICAM-1 was seen in follicular epithelial cells in association with folliculotropic LFA-1 lymphocytes, with concurrent decrease of ICAM-1 expression on epidermal keratinocytes.54 Follicular MF should be distinguished from so-called idiopathic follicular mucinosis.50,55,56 The latter condition, in contrast to follicular MF, usually affects younger patients and as a rule occurs as solitary lesions.53,57 Histological findings include abundant mucin deposition within the hair follicles, sometimes leading to their destruction, and lymphohistiocytic perifollicular infiltrates.52 The disease usually follows a benign course with complete remission after treatment, but cases with persistent lesions and even ‘transformation’ into overt MF have been described.58 The distinction between follicular MF and idiopathic follicular mucinosis on clinicopathological grounds may sometimes be difficult, as follicular MF may also occur in young patients and may present itself as solitary lesions.59– 61 Moreover, some investigators have demonstrated the presence of monoclonal T-cell populations in a portion of lesions of idiopathic follicular mucinosis.53,62 Future studies are necessary to establish the significance of these findings and clarify the relationship of follicular MF and idiopathic follicular mucinosis.

Syringotropic MF Adnexotropism in MF is not confined to hair follicles. Tropism of neoplastic lymphocytes to eccrine glands can rarely be observed in classical MF.63 In the syringotropic variant of MF this feature is prominent, with dense perieccrine infiltrates of small cerebriform cells invading both the secretory and the ductal portions of hyperplastic eccrine ducts (fig. 11).64 The irregular proliferation of small eccrine epithelial islands infiltrated by lymphocytes may resemble small aggregations of ‘eccrine spiradenoma en miniature’.65 The infiltrate may also invade the epidermis focally, but epidermotropism is not a marked feature and Pautrier’s microabscesses are not usually seen. Sometimes hair follicles may be concurrently involved or even destroyed by the neoplastic infiltrate (syringolymphoid hyperplasia with alopecia); follicular mucinosis is not usually seen. Clinically, patients present with red–brown patches, slightly infiltrated scaling plaques or small red- or skin-coloured papules. There are no predilection sites. Hair loss in the affected areas is observed frequently. Anhidrosis is found in approximately one-third of

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fig. 11 Syringotropic mycosis fungoides: lymphoid infiltration of eccrine glands that show mild hyperplasia and irregular proliferation.

cases.66–68 Ulceration is extremely rare. Remarkably, all patients reported to date have been men. The clinical presentation, expression of CD4 by the neoplastic cells with small cerebriform cytology and monoclonal rearrangement of TCR genes, indicates that this condition belongs to the spectrum of MF, although the more general term ‘syringotropic CTCL’ may be used.64 Like the situation with follicular MF and idiopathic follicular mucinosis, syringotropic CTCL should be distinguished from idiopathic forms of syringolymphoid hyperplasia with alopecia. Lesions in the idiopathic disease lack atypical lymphocytes and harbour no dominant T-cell clones. Some investigators suspect that the idiopathic form of the disease may be part of the early spectrum of the lymphoma form.68

Bullous/vesicular MF Bullous MF is seen in elderly people (average age 66 years) and has no gender predominance.69 It is manifested clinically as flaccid or tense, often multiple or even generalized, blisters appearing either on normal skin, on an erythematous base or within typical plaques and tumours of MF. Trunk and limbs are the sites of predilection. Flaccid bullae can sometimes demonstrate a positive Nikolsky sign.70 –75 If the blisters are accompanied by typical lesions of MF or patients disclose a previous history suggestive of MF, the diagnosis of MF can be readily established. Otherwise, a patient with bullous MF may pose a diagnostic problem. One of us (G.B.) has observed two patients with bullous MF in whom clinical features resembled erythema multiforme (targetoid appearance of skin lesions)3 (fig. 12). Histologically, all common features of MF (epidermotropism, cerebriform lymphocytes, etc.) are seen in the bullous variant. Blisters may occur in various locations—subcorneal, intraepidermal and subepidermal (fig. 13). The exact mechanism of blister formation is not clear. Negative immunofluorescence studies (both direct and indirect) militate against an

fig. 12 Bullous mycosis fungoides: multiple bullous lesions in the background of pre-existing patches and plaques. Some lesions have a targetoid appearance.

autoimmune process, although acantholysis may be seen. The following explanations for bulla formation have been proposed: (1) an intraepidermal blister may appear as a result of confluence of Pautrier’s microabscesses; (2) a subepidermal blister may be caused by accumulation of neoplastic lymphocytes in the basal layer leading to loss of coherence between the basal keratinocytes and basal lamina; and (3) normal cohesion of keratinocytes may be affected by the release of lymphokines by neoplastic cells.69 Bullous lesions in MF seem to indicate a poor prognosis, as almost 50% of the patients died within 1 year after the appearance of the blisters.72

Granulomatous MF and granulomatous slack skin Granulomatous MF is another unusual subtype, characterized by the histological presence of a granulomatous reaction. Clinically, a granuloma corresponds to a papule or nodule but may have no clinical equivalent and may be found in histological sections from patients with various clinical forms of MF: classical, erythrodermic, follicular, hyperpigmented, etc. The

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fig. 14 Granulomatous mycosis fungoides: a granulomatous reaction with foreign body giant cells within the dermal infiltrate.

fig. 13 Bullous mycosis fungoides: prominent intraepidermal vesiculation. Dense neoplastic infiltrate in the upper dermis.

granulomatous reaction in MF can adopt several histological patterns, namely (1) sarcoidal pattern, (2) granuloma annularelike pattern and (3) granulomatous pattern with multinucleated giant cells. In the sarcoidal pattern naked epithelioid granulomas are seen.76,77 In the granuloma annulare-like variant (also referred to as ‘interstitial’ MF) there is a dermal interstitial infiltrate of lymphocytes with rare histiocytes that resemble the interstitial form of granuloma annulare or inflammatory morphea. Epidermotropic lymphocytes are present at least focally in all cases. Increased dermal mucin deposition can also be demonstrated. The presence of additional skin lesions with typical MF features and the detection of T-cell clones enable this variant to be distinguished from granuloma annulare.78,79 The third pattern is typified, as its name implies, by the presence of multinucleated giant cells, usually of the foreign body type. Langerhans’ cells and Touton cells have also been described (fig. 14).80– 83 Emperipolesis can be seen. When granulomatous changes occur in patients with well-established MF, they do not pose any diagnostic problem. However, when they appear as an initial sign or when extensive granulomas obscure the underlying neoplastic lymphoid infiltrates, the diagnosis may be a challenge.

fig. 15 Granulomatous slack skin: an area of infiltration, discoloration and atrophy in the groin of a young adult.

The prognostic and clinical significance of a granulomatous reaction in MF remains uncertain. Initially, a protective role of a granulomatous reaction was claimed. However, later studies gave evidence that granulomatous MF may have an aggressive course with rapid extracutaneous spread and death.84 A recent analysis of the literature revealed that nearly 40% of the reported patients with granulomatous MF died of the disease, and in half of them death occurred within 5 years of the onset of the skin lesions.85 The exact cause of granuloma formation in MF is not clear but may be related to the treatment with interferon-alpha in some instances. Granulomatous slack skin (GSS) is closely related to granulomatous MF but has a unique constellation of clinicopathological features and therefore may be considered as a distinct entity. Clinically, GSS is typified by slowly developing, bulky, infiltrated folds of atrophic skin in flexural areas, mainly in the groin and axilla (fig. 15). Histologically, there is a dense epidermotropic, diffuse or band-like infiltrate in the upper and mid-dermis composed of small to large cerebriform lymphocytes with

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T-helper phenotype. The specific finding is the presence of multinucleated giant cells containing 20 –30 nuclei arranged in a wreath-like fashion (fig. 16). Some of the cells engulf the lymphoid cells (emperipolesis) and contain degenerated elastic fibres in their cytoplasm (fig. 17). The giant cells may form aggregates or may be scattered throughout all the layers of the dermis. Elastic fibres are almost totally absent.86–89 On occasion, involvement of large vessels occurs. A similar granulomatous

reaction with multinucleated giant cells may be observed in the tissue around lymph nodes or in internal organs.90 Dominant T-cell clones in GSS can be found in the skin and sometimes in lymph nodes.90 –92 Granulomatous MF differs from GSS clinically in the absence of bulky skin lesions and histologically in the lack of giant cells with a peculiar and characteristic wreath-like arrangement of nuclei and of elastolysis and elastophagocytosis (although reduction of elastic fibres within the area of infiltrate can sometimes be detected in MF).93 In some instances GSS is followed by Hodgkin’s lymphoma.94 –96

Hypopigmented MF Hypopigmented MF is often seen in young, dark-skinned patients of Indian or African-American origin, although it may sometimes be observed in light-skinned people.97–104 Patients present with asymptomatic or slightly pruritic, nonscaly patches with irregular borders (fig. 18). In some instances, typical patches, plaques or tumours may accompany the hypopigmented lesions.105–108 If this is not the case, MF is rarely

fig. 16 Granulomatous slack skin: a diffuse dermal infiltrate containing multinucleated giant cells with nuclei in a wreath-like fashion.

fig. 17 Granulomatous slack skin: giant cells phagocyting neoplastic lymphocytes (emperipolesis).

fig. 18 Hypopigmented mycosis fungoides: hypopigmented patches in a dark-skinned patient.

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fig. 20 Poikilodermic mycosis fungoides: atrophy of the epidermis with loss of the rete ridges, a band-like infiltrate of small cerebriform lymphocytes admixed with melanophages and dilation of blood vessels.

In addition, the majority of melanosomes are of the spherical type and incompletely melanized. Such ultrastructural changes are not specific for hypopigmented MF and are found in a variety of acquired hypopigmentary disorders.111,112

Poikilodermic MF

fig. 19 Poikilodermic mycosis fungoides: an area of poikiloderma atrophicans vasculare.

suspected, as the differential diagnostic considerations may include pityriasis versicolor, pityriasis alba, vitiligo, leprosy, sarcoidosis, postinflammatory hypopigmentation, etc. The histological findings as well as the clinical course and prognosis in hypopigmented MF are similar to those of the classical patchstage disease.100 Recent studies have shown that the neoplastic cells in hypopigmented MF often express CD8.109 In response to treatment, perifollicular repigmentation may be seen. On rare occasions, vitiligo-like leucoderma may occur in MF patients with otherwise typical MF lesions following treatment with psoralen plus UVA (PUVA). In such cases, the depigmentation is limited to the areas of pre-existing lesions.110 The peculiar clinical changes might result from a decreased transfer of melanosomes from melanocytes to keratinocytes and melanocyte degeneration as evidenced by electron microscopic studies. These degenerative changes in the melanocytes include marked dilatation of rough endoplasmic reticulum and swelling of mitochondria with loss of cristae and cytoplasmic vacuolation. More severely affected melanocytes demonstrate extensive cytoplasmic vacuolation and may undergo destruction.

A subset of patients with an otherwise typical clinical picture of MF may develop poikilodermic lesions characterized by alternating hypo- and hyperpigmentation, dryness, atrophy and telangiectasia (poikiloderma atrophicans vasculare). These lesions often develop slowly at the sites of pre-existing patches, usually in the areas where the skin is chronically rubbed by clothes, and are accompanied by otherwise typical patches and plaques of MF elsewhere (fig. 19). In some patients, the poikilodermic areas can predominate or even be the only finding.113 –116 Patients with universal poikiloderma involving the whole integument have been reported.117 A biopsy from poikilodermic areas will show histological findings similar to those seen in long-standing patch or plaque lesions. Additional histopathological changes typical for poikiloderma include atrophy of the epidermis with flattening or loss of rete ridges, subtle to moderate vacuolar alteration of the basal layer with loss of pigment, increased numbers of melanophages in the papillary and upper reticular dermis and dilatation of superficial blood vessels containing erythrocytes (fig. 20).117

Hyperpigmented MF This variant of MF is characterized by diffuse macular hyperpigmentation (resembling so-called ashy dermatosis) as the only clinical feature, not associated with poikiloderma atrophicans vasculare or regression of pre-existing lesions.118,119 Histologically,

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abundant melanin is present in the basal layer and focally in the spinous layer. Ultrastructural studies have demonstrated the presence of giant melanin granules in neoplastic lymphocytes, macrophages, keratinocytes and Langerhans’ cells of the epidermis.118 Melanin granules in Langerhans’ cells have been found to be located either within lysosomes or being encircled by Langerhans’ bodies. These findings may account for the peculiar clinical appearance of this type of MF.

Unilesional MF and unilesional pagetoid reticulosis (Woringer–Kolopp disease) Unilesional MF is typified by the presence of a single contiguous area of involvement covering less than 5% of the body surface.120 The lesions are usually found in body regions typical for classical MF, with breast, axilla and buttocks being the most common sites.120 Histopathological findings are identical to those seen in classical MF.121–124 Patients with unilesional MF demonstrate an excellent response to topical chemotherapy or irradiation. Recurrences may occur after surgical excision. The relationship between unilesional MF and unilesional pagetoid reticulosis (Woringer–Kolopp disease, WKD) is not clear. WKD typically manifests itself as a solitary, slowly growing plaque mostly in the acral location. The histological hallmark of the disease is striking epidermotropism of small- to medium-sized lymphocytes with cerebriform nuclei and focal spongiform disaggregation of markedly acanthotic epidermis. WKD has an indolent course.125–129 MF and WKD have some distinct histopathological and immunophenotypical features. WKD is distinguished histologically from MF in the presence of marked hyperkeratosis, prominent pagetoid epidermotropism of somewhat larger cerebriform cells, and paucicellular dermal infiltrate lacking eosinophils (fig. 21). The immunophenotype of neoplastic lymphocytes in this condition is more variable than in MF. The neoplastic cells in WKD may express CD4, CD8 or be CD4/CD8 double negative. The neoplastic cells in WKD demonstrate a higher proliferation rate (> 30%) in comparison to lymphocytes in patch- or plaque-stage MF (< 10%). Finally, in some cases infiltrates in WKD may contain high numbers (> 50%) of CD30+ cells, whereas such CD30 reactivity is never observed in non-transformed MF.125,126,128,129 The disseminated form of pagetoid reticulosis (Ketron– Goodman disease) is now regarded by many as MF as it shows similar clinical behaviour. Furthermore, some cases reported in the past as Ketron–Goodman disease may in fact represent primary cutaneous CD8-positive epidermotropic cytotoxic T-cell lymphoma.

MF palmaris et plantaris Involvement of the palms and soles occurring at some time in the course of MF is seen in 11.5% of cases.130 A subset of MF

fig. 21 Localized pagetoid reticulosis (Woringer–Kolopp disease): marked epidermotropism of small- to medium-sized lymphocytes surrounded by a clear halo.

patients (0.6%) present with lesions limited to, predominantly affecting, or initially presenting on the palms and/or soles, a condition referred to as mycosis fungoides palmaris et plantaris.130 Clinical variations include annular and hyperpigmented patches and plaques,130,131 hyperkeratotic lesions,132–134 vesicles or dyshidrotic lesions,71 pustules,135–137 verrucous changes,138 psoriasiform plaques,139 ulceration140 and nail dystrophy.134 The lesions are either strictly confined to the palms and/or soles or may extend onto the feet, arms and fingers (fig. 22). If these changes are not accompanied by typical MF lesions elsewhere on the body, the clinical diagnosis is usually challenging. Histopathological findings are usually compatible with typical MF, and demonstration of monoclonal rearrangements of TCR genes enables the correct diagnosis to be reached. Differential diagnostic considerations include mycotic infections, dyshidrotic eczema, contact dermatitis, palmoplantar psoriasis, verrucae, hypertrophic lichen planus, and granuloma annulare. The course of this MF subtype is usually indolent. The disease remains confined to the initial area of involvement in most cases

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fig. 22 Mycosis fungoides palmaris et plantaris: hyperkeratotic lesions on the sole. Extension of the lesions onto the dorsal aspect of the foot.

but extension to the limbs and trunk can occur, although no extracutaneous involvement has been reported.

Hyperkeratotic/verrucous MF Hyperkeratotic and verrucous changes may be found not only in patients with MF palmaris et plantaris.141 Hyperkeratotic/ verrucous MF manifests itself as hyperkeratotic and verrucous plaques which occur on lower legs, face and trunk and may or may not be accompanied by classical MF lesions or involvement of palms and soles3,142–144 (fig. 23).

Vegetating/papillomatous MF The lesions of vegetating/papillomatous MF (sometimes this subtype is also referred to as acanthosis nigricans-like) arise in flexural areas (axillae, groin), neck and breast (nipple, areolae).145–147 They may resemble acanthosis nigricans or seborrhoeic keratosis, depending on their configuration, size and colour. Histologically, there is papillomatosis, marked acanthosis that may have an appearance similar to that seen in seborrhoeic keratosis (interconnected rete ridges, horny pseudocysts), and a band-like or diffuse infiltrate of atypical lymphocytes (small, convoluted or medium-sized blast-like cells).145–147

Pigmented purpura-like MF Patients with this variant of MF present clinically, as the name suggests, with persistent pigmented purpuric lesions.148 On histological examination, there usually is a lichenoid band-like infiltrate composed mainly of small cerebriform lymphocytes accompanied by substantial numbers of siderophages, extravasated erythrocytes and some histiocytes.149–153 The lymphocytes invade the epidermis with typical lining-up in the basal layer. The majority of the cells are CD4+; some express CD8. Epidermal changes are variable but spongiosis and apoptosis are not seen. Monoclonal rearrangements of TCR genes can be demonstrated in a subset of cases; however, the presence of a

fig. 23 Hyperkeratotic/verrucous mycosis fungoides: massive hyperkeratotic lesions.

dominant T-cell population in these patients does not automatically imply MF.151 Monoclonal T-cell populations have also been demonstrated in purpuric drug eruptions (‘atypical pigmented purpura’).152 Therefore, a close follow-up is crucial to distinguish between benign pigmented purpuric dermatoses and this type of MF.

Pustular MF Pustular MF is marked by pustular eruptions that may be limited to palmoplantar areas or generalized.135–137,154 Histologically, there are intra-epidermal spaces filled with a mixture of atypical lymphocytes, neutrophils and eosinophils. The proportions of the above cell types are variable, and the inflammatory cells can outnumber the neoplastic ones.4,155 IL-8 has been suggested to play a role in the development of pustular lesions in MF.156

Ichthyosiform MF Ichthyosiform MF is a rare subtype, which, in a recent series, represented 1.8% of MF cases.157 It presents itself clinically as

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widespread ichthyosiform lesions often accompanied by comedo-like lesions and/or follicular keratotic papules. These ichthyosiform skin lesions favour the extremities, but the whole body surface may be involved. Pruritus is prominent and excoriations are common.157,158 While the ichthyotic changes are usually the only manifestations of this MF variant, the combination of classical MF and acquired ichthyosis (as a paraneoplastic phenomenon) has been documented.159,160 Histologically, the ichthyosiform areas demonstrate compact orthokeratosis, hypogranulosis and a band-like epidermotropic infiltrate composed of small cerebriform lymphocytes, whereas a biopsy from the follicular papules will display cyst-like dilated ostia of hair follicle with cornified plugging and infiltration of the follicular epithelium by neoplastic lymphocytes. No deposition of mucin within the follicular epithelium is found. Oral retinoids, in combination with PUVA or UVA therapy, have been shown to be the most effective treatment for this subtype of MF.157,158

Extracutaneous involvement in MF As described earlier, in advanced stages of MF an extracutaneous spread with involvement of various internal organs may occur (fig. 24).9,16 On very rare occasions, MF involves extracutaneous compartments such as the oral cavity (tongue, oral mucosae), oesophagus, breast, eyes and the central nervous system before large-cell transformation.159 – 171 As typical skin lesions are usually also present, the diagnosis should be straightforward. In the oral cavity, both tongue and mucosae may be affected. The incidence of tongue involvement in MF is estimated to be lower than 1%, with approximately 30 cases reported. It is a poor prognostic sign, as all reported patients died within 3 years after the appearance of their oral lesions.72,172,173 Histopathologically, features typical for MF (epitheliotropic infiltrates composed of small- to mediumsized cerebriform lymphocytes) are demonstrable in extracutaneous lesions.

fig. 24 Mycosis fungoides: diffuse infiltration of the tongue. A tumour in the vicinity of the mouth.

MF in childhood and adolescence MF is not purely a disease of the elderly. A thorough history taken from adult patients may reveal the onset of symptoms during childhood or adolescence (younger than age 20). The incidence of MF starting at an early age has been estimated to range from 1.8% to 7%.174 –178 In contrast to MF in adults, MF in childhood and adolescence does not show a prevalent male affection. A recent series has even revealed a striking female predominance.179 Features typical for ordinary MF as well as various atypical clinical variants have been reported. Among the latter, the hypopigmented form appears to be over-represented. The majority of patients present with stage 1A and 1B disease and therefore have an excellent prognosis with survival rates similar to that seen in the background population.178,180 Progression to plaque-stage disease and death of disease have been documented in retrospective studies.177,178 There are no factors that predict tumour progression in young MF patients. In addition to the above-described atypical forms of MF there are anecdotal reports of the disease presenting as or mimicking keratosis lichenoides chronica,181 pityriasis lichenoides,182 perioral dermatitis,183 tinea corporis,184 psoriasis,185 ischaemic foot186 and ‘invisible’ MF.187,188

D’emblée MF The d’emblée form of MF has in the past been referred to as a condition typified by the sudden multifocal development of cutaneous tumours without preceding patches or plaques. Nowadays it is agreed that such cases represent primary cutaneous pleomorphic, medium-sized or large-cell T-cell lymphomas, CD30+ or CD30 –.

Summary The clinicopathological spectrum of MF is wide and ranges from lesions with clear-cut features of this lymphoma to subtle changes or lesions mimicking various inflammatory dermatoses. This diversity sometimes makes the diagnosis of MF and especially its atypical forms challenging. In a patient with MF there is no single criterion that the definitive diagnosis of MF can be based on. Even an integrated assessment of all available data (clinical features, histopathological findings, immunophenotype, molecular biology) may sometimes not be enough for the correct diagnosis. In a subset of cases only the follow-up is decisive and this fact should be accepted. We do not suggest that all above-described variants of MF deserve a delineation as separate entities in lymphoma classifications. However, the recognition of these forms is important because of the above-mentioned similarity to inflammatory dermatoses and therapeutic as well as prognostic aspects. MF is not the only cutaneous lymphoma demonstrating such variations in clinicopathological manifestations. Other examples

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are primary cutaneous CD30-positive T-cell lymphoproliferative disorders and NK-cell neoplasms. The diversity of MF is certainly the most prominent of them all. There is no satisfactory explanation for this phenomenon. A concept of multistep evolution of CTCL might be an explanation.189,190 If MF does arise in the background of a chronic inflammation as a response to chronic antigen stimulation and subsequently progresses due to a series of mutations, this would explain why many MF variants clinically resemble various inflammatory dermatoses, especially in early stages, but show unequivocal clinicopathological features of a neoplastic process with time.

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