MICOSI FUNGOIDE CLINICA.pdf

Actas Dermosifiliogr. 2017;108(3):192---208 REVIEW Clinicopathologic Variants of Mycosis Fungoides夽 H. Muñoz-González, A.M. Molina-Ruiz,∗ L. Requena Servicio de Dermatología, Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain Received 17 May 2016; acce...

Actas Dermosifiliogr. 2017;108(3):192---208 REVIEW Clinicopathologic Variants of Mycosis Fungoides夽 H. Muñoz-González, A.M. Molina-Ruiz,∗ L. Requena Servicio de Dermatología, Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain Received 17 May 2016; accepted 4 August 2016 Available online 28 February 2017 KEYWORDS Abstract Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. The Cutaneous clinical course of the disease is typically characterized by progression from a nonspecific phase lymphomas; of erythematous macules to the appearance of plaques and ultimately, in some patients, tumors. Mycosis fungoides; However, numerous clinical and histopathologic variants of MF with specific therapeutic and Variants; prognostic implications have been described in recent decades. Clarification of the differential Dermatopathology diagnosis can be frustrated by the wide range of clinical manifestations and histopathologic patterns of cutaneous infiltration, particularly in the early phases of the disease. In this paper, we review the main clinical, histopathologic, and immunohistochemical characteristics of the variants of MF described in the literature in order to facilitate early diagnosis of the disease. © 2016 Elsevier España, S.L.U. and AEDV. All rights reserved. PALABRAS CLAVE Variantes clínico-patológicas de micosis fungoide Linfomas cutáneos; Micosis fungoide; Resumen La micosis fungoide (MF) es el linfoma primario cutáneo de células T más frecuente. Variantes; La evolución clínica clásica de la enfermedad se caracteriza por la progresión desde una fase Dermatopatología inespecífica de máculas eritematosas a la aparición de placas y, finalmente, tumores en algunos pacientes. Sin embargo, a lo largo de las últimas décadas se han descrito numerosas variantes de MF, tanto desde el punto de vista clínico como histopatológico, con implicaciones terapéuticas y pronósticas específicas. El diagnóstico diferencial se ve dificultado así ante el amplio abanico de manifestaciones clínicas y patrones histopatológicos de infiltración cutánea, especialmente en fases precoces de la enfermedad. Este artículo revisa las principales características clínicas, histopatológicas e inmunohistoquímicas que definen las distintas variantes de MF descritas en la literatura con el objetivo de facilitar el diagnóstico temprano de MF. © 2016 Elsevier España, S.L.U. y AEDV. Todos los derechos reservados. 夽 Please cite this article as: Muñoz-González H, Molina-Ruiz AM, Requena L. Variantes clínico-patológicas de micosis fungoide. Actas Dermosifiliogr. 2017;108:192---208. ∗ Corresponding author. E-mail address: [email protected] (A.M. Molina-Ruiz). 1578-2190/© 2016 Elsevier España, S.L.U. and AEDV. All rights reserved. Clinicopathologic Variants of Mycosis Fungoides 193 Introduction the superficial dermis, and on occasions they are surrounded by a pale cytoplasmic halo. These morphologic features are Mycosis fungoides (MF) is the most common primary T- highly indicative of MF, but they are not consistent, and cell cutaneous lymphoma and accounts for almost 50% of repeat skin biopsies over time are often necessary to estab- all primary cutaneous lymphomas.1 Described for the first lish a definitive diagnosis of patch-stage MF.4 time in 1806 by the French dermatologist Jean Louis Alib- ert, classic MF starts with a nonspecific phase consisting Plaque-Stage MF of erythematous macules that can last for years. In sub- sequent phases, patients develop plaques and, in some Plaque-stage MF is characterized by well-demarcated ery- cases, tumors. The name mycosis fungoides refers to the thematous or dark brown plaques that are often pruritic and mushroom-like appearance of the tumors. Enlarged lymph accompanied by scaling. They generally affect a large area nodes, visceral involvement, and transformation to large- of skin (Fig. 1D). Plaques and characteristic macules from cell lymphoma are less common findings that are typically earlier stages frequently coexist in the same or different seen in advanced stages of the disease. Numerous clini- areas.5,6 cal and histopathologic variants of MF have been described Plaque-stage MF has similar histopathologic features to in recent decades. Although some of these variants have patch-stage MF but it has a denser band-like lichenoid lym- been reported as isolated cases, others have greater clin- phocytic infiltrate in the superficial dermis. This infiltrate is ical relevance due to their relative frequency and their primarily composed of small and medium-sized lymphocytes therapeutic and prognostic implications. The wide range with pleomorphic hyperchromatic nuclei and numerous con- of clinical and pathological presentations of early-stage MF volutions that lend it a cerebriform appearance (Fig. 1E requires a broad differential diagnosis as early lesions can and F). Epidermotropism is frequently more pronounced in mimic many of the patterns seen in cutaneous inflammatory plaque-stage than in patch-stage MF and is characterized disorders. by the presence of atypical lymphocytes in the epidermis In this article, we review the main clinical, histopatho- that occur in isolation or form collections known as Pautrier logic, and immunohistochemical characteristics that help to microabscesses. Other common findings include epidermal establish a correct diagnosis of MF, particularly in the early hyperplasia, papillary dermal fibrosis, and some eosinophils stages of disease. We also describe the distinctive clinical and plasma cells in the accompanying inflammatory infil- and pathological features that define the different variants trate. of MF. Tumor-Stage MF Classic MF Skin tumors are the key clinical feature of tumor-stage MF has traditionally been defined as a 3-stage disorder MF and they frequently coexist with patches and plaques characterized by the progressive appearance of patches, (Fig. 1G). The absence of patches and plaques should lead to plaques, and tumors. Not all patients, however, pass through a reassessment of diagnosis and the inclusion of other more these 3 stages. Some remain in the plaque stage, showing no aggressive non-MF cutaneous lymphomas in the differential signs of disease progression, while others develop patches, diagnosis. MF tumors are characterized by significant verti- plaques, and tumors as a presenting form of the disease. cal growth, giving rise to smooth reddish-brown or bluish-red nodules that can reach a size of several centimeters and become ulcerated or infected.7 Patch-Stage MF Histopathologic findings include a diffuse nodular lym- phocytic infiltrate formed by large pleomorphic lymphocytes Patch-stage MF is clinically characterized by the presence with hyperchromatic nuclei and prominent nucleoli occupy- of asymmetric, irregular, erythematous macules and patches ing the full thickness of the dermis and possibly extending occasionally associated with atrophy and/or telangiectasia.2 into the subcutaneous tissue (Fig. 1H and I). The cells in The lesions are generally asymptomatic or mildly pru- the infiltrate frequently have a high proliferative index and ritic and disappear spontaneously, without leaving residual typical and atypical mitotic figures are abundant. Pautrier lesions (Fig. 1A). Patch-stage MF can last for years, with microabscesses and epidermotropism are normally absent in no signs of progression. It is not associated with worse out- the tumor stage of MF. comes than other forms of MF and patients have a similar life expectancy to the general population.3 The histopathologic features of patch-stage MF include Diagnosing MF scarce lymphocytes scattered through the basal layers of the epidermis, accompanied by focal parakeratosis, Pathologic diagnosis of early-stage MF is challenging not only papillary dermal fibrosis, and a larger population of because of the subtle nature of the histopathologic find- lymphocytes arranged in a band-like pattern along the ings, but also because of overlapping with features seen dermal-epidermal junction. Additional findings include a in other inflammatory skin disorders. This is further com- predominantly lymphocytic perivascular, periadnexal, or plicated by the absence of certain characteristic clinical subepidermal infiltrate with eosinophils and some plasma and histopathologic findings in early MF. Pautrier microab- cells (Fig. 1B and C). Intraepidermal lymphocytes are gener- scesses, for instance, are observed in less than 25% of cases, ally larger and more pleomorphic than lymphocytes found in atypical lymphocytes are found in less than 10% of cases, and 194 H. Muñoz-González et al. Figure 1 Classic mycosis fungoides (MF). A, Photograph of patch-stage MF lesions. B, C, Typical histopathologic findings in patch- stage MF showing an epidermotropic infiltrate composed of atypical lymphocytes in the papillary dermis. D, Photograph of plaque- stage MF lesions. E,F, Typical histopathologic findings in plaque-stage MF; they are similar to those seen in patch-stage MF, but there is a denser lichenoid lymphocytic infiltrate with a band-like distribution in the superficial dermis, together with marked epidermotropism and Pautrier microabscesses. G, Photograph of tumor-stage MF. H, I, Characteristic histopathologic features in tumor-stage MF, including a diffuse lymphocytic infiltrate of large, irregular lymphocytes occupying the full dermis. epidermotropism, a hallmark feature of MF, may be absent conditions and are probably a result of chronic T-cell in up to 4% of cases.1,8 stimulation.11 In 2005, the International Society for Cutaneous Despite the lack of specific cellular and molecular mark- Lymphomas developed a diagnostic algorithm combining ers for confirming early-stage MF, 19 different genes were clinical, histopathologic, immunohistochemical, and molec- recently found to be significantly upregulated in early MF ular criteria to facilitate the diagnosis of early-stage MF compared with other chronic inflammatory disorders.12 Two (Table 1)9 ; the algorithm supports the use of serial skin biop- of these genes----programmed cell death protein 1 gene sies in equivocal cases.10 (PDCD1) and the thymocyte selection-associated high mobil- Immunohistochemical analysis of neoplastic T cells, com- ity group box gene (TOX)----are of particular interest due bined with clinical and histopathologic findings, can aid to their capacity to discriminate between early MF and diagnosis. Neoplastic cells in MF are typically CD4+ , with benign inflammatory conditions. TOX appears to be both variable loss of other T-cell markers, such as CD2, CD3, a sensitive and specific immunohistochemical marker for CD5, CD7, and CD26. Within this group, loss of CD7, the early diagnosis of MF and displays an intense diffuse followed by CD5, is the most common finding. A CD8+ nuclear staining pattern that is not seen in other inflamma- T-cell phenotype may be detected in up to 20% of cases. tory skin disorders. TOX-positive cells have atypical nuclei Monoclonal T-cell receptor (TCR) gene rearrangement may and are seen in both the epidermis and papillary dermis also point to a diagnosis of early-stage MF. Unfortunately, of skin biopsy specimens from patients with early-stage neither TCR gene rearrangement nor loss of CD7 expres- MF, as well in Pautrier microabscesses. A close correlation sion permits a definitive diagnosis, as these nonspecific has been found between TOX staining and neoplastic cells findings are also seen in other benign inflammatory skin in MF.12 Clinicopathologic Variants of Mycosis Fungoides 195 Table 1 Algorithm for Diagnosing Early-Stage Mycosis Fungoides. Criteria Scorea Clinical criteria 2 points for main criterion plus 2 additional criteria Main criterion Persistent and/or progressive patches and plaques 1 point for main criterion plus 1 additional criterion Additional criteria Nonphotoexposed areas Variable size and shape Poikiloderma Histopathologic criteria 2 points for main criterion plus 2 additional criteria Main criterion Superficial lymphocytic infiltrate 1 point for main criterion plus 1 additional criterion Additional criteria Epidermotropism without spongiosis Atypical lymphocytes (cells with large, hyperchromatic, and irregular or cerebriform nuclei) Molecular biology criteria 1 point for clonality Monoclonal T-cell receptor gene rearrangement Immunopathologic criteria 1 point for at least 1 criterion < 50% CD2+ , CD3+ , and/or CD5+ T cells < 10% CD7+ T cells Dermal/epidermal discordance in expression of CD2, CD3, CD5, or CD7b a A score of at least 4 is required to diagnose mycosis fungoides, regardless of the combination of clinical, histopathologic, biomolecular, and immunohistochemical criteria. b Loss of T-cell antigen expression in the dermis. Source: Adapted from Pimpinelli et al.9 Clinicopathologic Variants of MF sometimes the only manifestation of MF, a thorough physi- cal examination often reveals the presence of characteristic The clinicopathologic variants of MF fall along a spectrum erythematous patches or plaques. ranging from clinical variants, which have distinctive clinical Classic histopathologic features of MF are common in the but similar histopathologic features to classic MF, to clin- hypopigmented variant, which is characterized by marked icopathologic variants, which have distinctive clinical and epidermotropism frequently associated with atypical CD8+ histopathologic features, to histopathologic variants, which T cells. Occasional nonspecific findings include a periad- can only be distinguished from classic MF by biopsy (Table 2). nexal and perivascular dermal lymphocytic infiltrate and Within this broad group, only folliculotropic MF, pagetoid psoriasiform hyperplasia in the epidermis (Fig. 2B-D). The reticulosis, and granulomatous slack skin were included characteristic immunophenotypic profile of hypopigmented in the latest international classification of cutaneous lym- MF is decreased CD7 expression and a greater presence of phomas published by the World Health Organization (WHO) CD1a+ Langerhans cells in the epidermis, although CD4+ cells in 2016. In this review, however, we describe the full spec- have also been described. CD30 expression is rare.13,15 trum of clinicopathologic variants, as familiarity with these The main entity that should be contemplated in the dif- will help to narrow the differential diagnosis for both der- ferential diagnosis is inflammatory vitiligo,16,17 which is also matologists and pathodermatologists. characterized by an epidermotropic CD8+ T-cell infiltrate. Integration of clinical and pathologic findings and regu- lar follow-up are often necessary to distinguish between Clinical Variants of MF hypopigmented MF and inflammatory vitiligo. It is important to include other skin disorders with hypopigmentation (e.g., Hypopigmented MF pityriasis alba) in the differential diagnosis. Hypopigmented MF is an uncommon clinical variant of MF characterized by hypopigmented macules and papules with- out atrophy (Fig. 2A). It is more common in patients with Erythrodermic MF a dark complexion and is one of the most frequent variants Erythrodermic MF is a variant of MF in which patients seen in childhood, although cases have also been reported with classic histopathologic features of MF develop ery- in adults.13 Hypopigmented MF has a better prognosis than throderma but do not meet the diagnostic criteria of the classic form of the disease and it responds favor- Sézary syndrome (Fig. 3).18 Although on rare occasions ably to phototherapy with narrowband UV-B, particularly in it may be the first manifestation of MF, erythroderma juvenile-onset MF.14 Lesions gradually regain pigmentation typically appears after the development of the character- following treatment. Although hypopigmented lesions are istic patches and plaques. It is frequently associated with 196 H. Muñoz-González et al. Figure 2 Hypopigmented mycosis fungoides. A, Photographs showing hypopigmented macules and plaques without cutaneous atrophy in a child. B, Panoramic view showing an infiltrate in the superficial dermis. C,D, Detailed view of the dermal infiltrate with atypical lymphocytes and epidermotropism. Figure 3 Erythrodermic mycosis fungoides. A, Photograph showing coexistence of erythroderma and MF plaques and tumors. B,C, Histopathologic images showing an epidermotropic inflammatory infiltrate in the papillary dermis with mildly atypical lymphocytes. Clinicopathologic Variants of Mycosis Fungoides 197 Table 2 Clinical, Clinicopathologic, and Histologic Variants and paraneoplastic ichthyosis in a patient with known MF. of Mycosis Fungoides. Histopathologic examination of paraneoplastic ichthyosis lesions will only show findings associated with ichthyosis, Clinical Variants i.e., the characteristic lymphocytic infiltrate seen in MF Hypopigmented mycosis fungoides will be absent. Infiltration of hair follicles by atypical lym- Erythrodermic mycosis fungoides phocytes, associated or not with follicular papules, may Ichthyosiform mycosis fungoides sometimes be seen, suggesting perhaps a closer association Mycosis fungoides palmaris et plantaris with folliculotropic MF.25 Papillomatous mycosis fungoides Papular mycosis fungoides MF Palmaris et Plantaris Solitary or unilesional mycosis fungoides MF palmaris et plantaris, another uncommon clinical variant Invisible mycosis fungoides of MF, is characterized by the exclusive involvement of the palms and soles in the form of patches, plaques, or tumors.26 Clinicopathologic variants The lesions can spread to the dorsum of the hands and feet and to the fingers, wrists, and toes. Onychodystrophy is Folliculotropic mycosis fungoides common. A patient with MF palmaris et plantaris will have Mycosis fungoides with eruptive infundibular cysts characteristic MF lesions in acral regions only. The condition Syringotropic mycosis fungoides follows an indolent course and involvement of deeper areas Granulomatous slack skin of the skin is unusual.27 Pagetoid reticulosis or Woringer-Kolopp disease The histologic findings of MF palmaris et plantaris are Poikilodermal mycosis fungoides (poikiloderma vasculare again similar to those seen in classic MF, contrasting with the atrophicans) atypical pagetoid lymphocytes and striking epidermotropism Bullous mycosis fungoides and dyshidrotic mycosis seen in pagetoid reticulosis (Woringer-Kolopp disease). fungoides Anetodermic mycosis fungoides Hyperpigmented mycosis fungoides Papillomatous MF Purpuric mycosis fungoides Filamentous or vegetating MF lesions are reminiscent of Pustular mycosis fungoides acanthosis nigricans or seborrheic keratosis; they are gen- Verrucous mycosis fungoides erally located in flexural regions such as the neck, the axillae, and the inguinal folds. Histopathologic findings Histopathologic variants include marked acanthosis and papillomatosis together with a band-like infiltrate composed of atypical lymphocytes that Granulomatous mycosis fungoides may or may not be epidermotropic.28,29 Interstitial mycosis fungoides Mycosis fungoides with large-cell transformation Papular MF Papular MF is a clinical variant of MF characterized by the presence of small non-folliculocentric papules and the inappropriate treatments, facilitating diagnosis.19 Classic absence of conventional MF patches and plaques (Fig. 4A).30 MF lesions reappear in patients with erythrodermic MF fol- Histopathologic findings are similar to those observed in lowing appropriate treatment of erythroderma. classic MF and have a characteristic patch-like distribution Erythrodermic MF can be distinguished from Sézary syn- (Fig. 4 B-D); there is no follicular involvement. Although drome, as patients will not have the typical blood alterations papular MF was originally described as a benign condition seen in Sézary syndrome; they may have enlarged lymph with a favorable long-term prognosis,31 there have been nodes but this is uncommon. Although both entities share reports of erythroderma appearing after relatively short hematology-oncology staging and classification criteria,20,21 periods of time and of rapid progression to the tumor recent studies have shown that they have different chro- stage.32 mosomal alterations22 and immunophenotypic profiles,23 Diagnosis is challenging given the absence of the typical demonstrating that they originate from 2 distinct popula- clinical manifestations of MF. The main entities to consider tions of lymphocytes and thus constitute separate entities. in the differential diagnosis are lymphomatoid papulosis and other primary cutaneous lymphoproliferative disorders. Ichthyosiform MF Papular MF lesions tend to be stable and characteris- Ichthyosiform MF is an uncommon clinical variant of MF. It tic features seen in lymphomatoid papulosis (spontaneous typically affects the extremities and is characterized by geo- regression, ulceration, hemorrhaging, and residual vari- metric plaques with a cobblestone pattern similar to that oliform scars) are absent. The infiltrate in papular MF seen in ichthyosis vulgaris.24 Ichthyosiform MF occasionally typically has a CD30− immunophenotype.33 occurs in association with follicular papules and other char- acteristic lesions of folliculotropic MF. Solitary or Unilesional MF Ichthyosiform MF has similar histopathologic findings Solitary or unilesional MF refers to an isolated macule, to classic MF combined with features of ichthyosis, such plaque, or nodule with indistinguishable histopathologic as hypogranulosis and hyperkeratosis.25 The detection of characteristics to those of classic MF; there is no evi- features from both entities in the same biopsy specimen dence of any other cutaneous lesions.34,35 The observation narrows the differential diagnosis down to ichthyosiform MF of a band-like inflammatory infiltrate accompanied by 198 H. Muñoz-González et al. Figure 4 Papular mycosis fungoides. A, Photograph showing small non-folliculocentric papules on a leg. B, Panoramic view showing a mild infiltrate in the papillary dermis. C,D, Detailed view of the dermal infiltrate with atypical lymphocytes and epidermotropism. isolated epidermotropic atypical lymphocytes but no other in the eyebrows with hair loss are also common. Follicu- histopathologic features requires consideration of local- lotropic MF is usually highly pruritic. The pruritus tends to ized pagetoid reticulosis, another variant of MF that also be refractory to treatment and, as occurs in tumor-stage manifests as isolated lesions but has different clinical and MF, is associated with poor prognosis.39,40 The follicu- histologic features.36 Solitary or unilesional MF is associated lotropic variant of MF mainly affects adults (predominantly with a favorable prognosis; it follows a benign course and males), although cases have been described in children and rarely progresses to more advanced forms. adolescents.20 Histopathologic features of folliculotropic MF include iso- Invisible MF PRURITO COME UNICO SINTOMO lated or aggregates of atypical lymphocytes in the outer root Invisible MF is a variant of MF in which histopathologic fea- sheath of the hair follicle (a phenomenon known as follicu- tures of classic MF are detected in normal-appearing skin; lotropism), in addition to a perivascular and periadnexal there are no visible skin lesions and the only symptom is pru- dermal inflammatory infiltrate of atypical lymphocytes, ritus. Skin lesions may remain absent for the entire course eosinophils, and plasma cells (Fig. 5 B-D). Although isolated of the disease.37 lymphocytes may be seen dotted through the epidermis, epidermotropism is not common in folliculotropic MF.41 A significant inflammatory infiltrate involving the eccrine Clinicopathologic Variants of MF sweat glands may be observed and should raise suspicion of extensive adnexal involvement. Another common finding is Folliculotropic MF mucinous degeneration of the follicular epithelium (follicu- Folliculotropic MF is one of the most common variants of MF lar mucinosis), which becomes more evident on staining with and has accounted for up to 10% of all forms of MF in some Alcian blue or other mesenchymal mucin stains. Immunohis- series.38 It is considered to be an entity in its own right, tochemical findings are similar to those seen in classic MF and was included in the WHO-EORTC (European Organiza- and CD30+ infiltrates are common.20 tion for Research and Treatment of Cancer) classification for cutaneous lymphomas20 and in the 2016 revision of the WHO classification of hematopoietic and lymphoid tumors.21 MF With Eruptive Infundibular Cysts Typical clinical manifestations of folliculotropic MF are A localized or generalized follicular eruption consisting of indurated erythematous plaques combined with follicular infundibular cysts and comedones has been described in papules and acneiform lesions including small cysts and some patients with MF and appears to be a rare man- comedones. Lesions are typically located on the head and ifestation of the disease.42---44 Because of their size and neck and are frequently associated with alopecia and on inflammatory appearance, the lesions may sometimes sim- occasions with mucinorrhea (Fig. 5A). Infiltrated plaques ulate tumor-stage lesions.45 MF with eruptive infundibular  Clinicopathologic Variants of Mycosis Fungoides 199 Figure 5 Folliculotropic mycosis fungoides (MF). A, Photograph showing follicular papules and acneiform lesions on the face and neck. B, Panoramic view showing an infiltrate around the hair follicles. C, D, Higher-magnification view showing aggregates of atypical lymphocytes in the outer root sheath of the hair follicle. cysts must be distinguished from folliculotropic MF, although condition traditionally known as syringolymphoid hyperpla- some authors consider the 2 variants to be part of the same sia is now considered to be syringotropic MF. spectrum of follicular involvement in MF.32 Histology shows the characteristic features of an infundibular cyst surrounded by a dense infiltrate formed Granulomatous Slack Skin primarily by atypical lymphocytes in the cyst wall. The Granulomatous slack skin is a very rare variant of MF. It appearance of infundibular cysts may be related to infil- is characterized by erythematous plaques that take the tration of follicular openings by neoplastic cells, causing form of frequently large folds of lax pendulous skin gen- subsequent blockage and dilation of the infundibula.42 erally located in flexural areas such as the axillae and groin (Fig. 7A).48 Its distinctive clinical and histopathologic features earned it a place in the latest WHO-EORTC classifi- Syringotropic MF cation for cutaneous lymphomas.20,21 It follows an indolent Syringotropic MF is an uncommon clinicopathologic vari- course and tends to recur after local excision. It is more com- ant of MF characterized by eccrine gland involvement. mon in young patients. Many patients with granulomatous Clinical manifestations include erythematous papules and slack skin have a second lymphoma, and Hodgkin disease is plaques that may or may not be accompanied by a fol- particularly common.20 licular eruption. The papules and plaques are sometimes Characteristic histopathologic findings include a diffuse hyperpigmented. Adnexal involvement frequently leads to granulomatous inflammatory infiltrate that occupies the anhidrosis and alopecia.46 Patients can have solitary or mul- full thickness of the dermis and occasionally extends into tiple syringotropic lesions, which may be accompanied by the subcutaneous tissue. The infiltrate is composed of classic MF lesions in other areas of the skin. Palmoplantar histiocytes, atypical lymphocytes, and giant multinucle- involvement is common. Syringotropic MF follows an indo- ated cells, which often contain large numbers of nuclei. lent clinical course. Another characteristic finding is a striking loss, or even The most characteristic histologic findings, which allow total absence, of elastic fibers, fragments of which can be the condition to be distinguished from folliculotropic MF, observed in the interior of the giant multinucleated cells are a dense infiltrate of atypical lymphocytes in the eccrine (elastophagocytosis) (Fig. 7B and C). Giant multinucleated glands and ducts and a variable degree of syringometapla- cells also frequently contain lymphocytes as a result of sia (squamous transformation of the glandular epithelium) phagocytosis or emperipolesis and there is a notable absence (Fig. 6).47 Epidermotropism and follicular involvement are of epidermotropism and Pautrier microabscesses. Granulo- common.46 Other less specific findings are a band-like matous MF is distinguished by the presence of small sarcoid inflammatory infiltrate and epidermal hyperplasia. The granulomas dotted through the dermis and the absence of ATTENZIONE PERHCE’ LA COMBINAZIONE ALOPECIA ANIDROSI PUO’ ESSERE UN SEGNO DI MF SIRINGOTROPICA 200 H. Muñoz-González et al. Figure 6 Syringotropic mycosis fungoides. A, Panoramic view showing band-like infiltrate in the reticular and periglandular dermis. B, Higher-magnification view showing dense infiltration of eccrine glands by lymphocytes. C, D, Higher-magnification view showing atypical lymphocytes surrounding an eccrine sweat gland with syringometaplasia. Figure 7 Granulomatous slack skin. A, Photograph showing an erythematous plaque in the form of a large pendulous skinfold in the axilla. B, Panoramic view showing a diffuse inflammatory infiltrate throughout the dermis and extending into the subcutaneous tissue. C, Higher-magnification view showing that the infiltrate is composed of histiocytes, atypical lymphocytes, and giant multinucleated cells with many nuclei. Clinicopathologic Variants of Mycosis Fungoides 201 Figure 8 Pagetoid reticulosis. A, Photograph showing a solitary erythematous, hyperkeratotic, psoriasiform plaque on the heel. B, Panoramic view showing epidermal hyperplasia, hyperkeratosis, and parakeratosis and an infiltrate in the papillary dermis. C,D, Higher-magnification view showing the marked epidermotropism of the infiltrate, formed by atypical pagetoid lymphocytes with large hyperchromatic nuclei. elastophagocytosis. However, the 2 variants are essentially Poikilodermal MF distinguished on clinical grounds.49 Poikilodermal MF, which is classically referred to as poikilo- derma vasculare atrophicans, is one of the most common variants of MF. It manifests as plaques with atrophy, Pagetoid Reticulosis hyperpigmentation, hypopigmentation, and telangiectasia Pagetoid reticulosis or Woringer-Kolopp disease is a rare covering a large area of skin. Compared with other vari- variant of MF characterized by slow growth, an indolent ants of MF, prognosis appears to be favorable and the lesions clinical course, and a favorable prognosis. It is included respond well to phototherapy (Fig. 9A).52 The most common in the latest WHO-EORTC classification for cutaneous areas affected are the breasts in women and the buttock lymphomas.20,21 It clinically manifests as a solitary lesion region in women and men. generally located in the acral areas of the extremities. The Histopathologic features of poikilodermal MF include epi- lesion is typically an erythematous plaque with a psoriasi- dermal atrophy with flattening of the dermal-epidermal form, hyperkeratotic appearance (Fig. 8A). The treatment junction, vacuolar degeneration of the basal layer, and a of choice is surgical excision or local radiation therapy. lichenoid epidermotropic infiltrate composed of atypical The presence of disease progression or extracutaneous lymphocytes. Other relevant findings are apoptotic kerati- involvement, classically referred to as disseminated page- nocytes, pigmentary incontinence, and dilated capillaries in toid reticulosis or Ketron-Goodman disease, is currently the superficial dermis (Fig. 9 B-D). Pautrier microabscesses considered to correspond to a more aggressive cutaneous are not usually present. Neoplastic cells frequently express lymphoma (epidermotropic cytotoxic T-cell lymphoma in a CD8+ immunophenotype.52 nearly all cases).20 Characteristic histopathologic findings of pagetoid retic- ulosis include an infiltrate with marked epidermotropism Bullous MF composed of atypical pagetoid lymphocytes with a large Bullous MF is a clinicopathologic variant of MF characterized hyperchromatic nucleus surrounded by a pale halo, in by bullous vesicular lesions that was described by Kaposi in addition to epidermal hyperplasia with hyperkeratosis and 1887.53 The lesions can be flaccid or tense and they usually parakeratosis (Fig. 8 B-D). Pagetoid reticulosis is often affect large areas of the trunk and extremities (Fig. 10A). characterized by a CD8+ immunophenotype with CD30 The rupture of bullae can cause superficial erosions. Bullous expression in most cases,50 although this is not associated lesions frequently coexist with classic MF lesions and can with a more aggressive biologic behavior.51 appear either as the first manifestation of MF or later.53,54 202 H. Muñoz-González et al. Figure 9 Poikilodermal mycosis fungoides. A, Photograph showing plaques with atrophy, hyperpigmentation, hypopigmentation, and telangiectasia on both buttocks. B, Panoramic view showing a lichenoid infiltrate in the papillary dermis. C, D, Higher- magnification view showing epidermal atrophy with flattening of the dermal-epidermal junction, an infiltrate composed of atypical lymphocytes with epidermotropism and dilatations, and dilated capillaries in the superficial dermis. Figure 10 Bullous mycosis fungoides. A, Photograph showing symmetric vesicular bullous lesions on the hands. B, Panoramic view showing intraepidermal bullae. C,D, Detailed view of the bullae, with atypical lymphocytes in the papillary dermis and epidermotropism. Clinicopathologic Variants of Mycosis Fungoides 203 Figure 11 A, Photograph showing a patient with atrophic plaques and atrophic nodules with a parchment-like surface. B, Panoramic view of a diffuse infiltrate occupying the entire dermis. C, Detailed view at a higher magnification of the infiltrate, showing atypical lymphocytes and elastophagocytosis. D, Orcein stain showing the absence of elastic fibers in the dermis. The term dyshidrotic MF has been used to describe bullae occasionally seen in association with other uncommon vari- confined to the palms and soles.55 ants of MF, but in this case, the hyperpigmentation is not Histopathologically, bullous MF is characterized by due to poikilodermic changes or residual hyperpigmentation intraepidermal or subepidermal blisters combined with from previous lesions.59 classic features of MF, such as atypical lymphocytes, epi- Histopathologic features include pigmentary inconti- dermotropism, and Pautrier microabscesses (Fig. 10 B-D). nence with abundant melanin granules in keratinocytes and Direct and indirect immunofluorescence results are nega- Langerhans cells60 together with numerous melanophages tive, helping to distinguish this variant from autoimmune in the papillary dermis and the classic features of MF. blistering diseases. Other causes of bullous lesions, such as Neoplastic cells tend to be located around the dermal- drugs or bacterial or viral infections, must be contemplated epidermal junction and display a characteristic CD8+ in the differential diagnosis.53,56 immunophenotype.61 Prognosis is poor and the 1-year survival rate following Hyperpigmented MF appears to follow an indolent, rela- onset of bullous-vesicular lesions is approximately 50%.53,57 tively nonaggressive course.59,61 Anetodermic MF Purpuric MF The term anetoderma refers to the progressive loss of der- Purpuric MF is clinically characterized by persistent pur- mal elastic tissue that results in atrophic plaques with puric lesions and histologically characterized by a band-like a characteristic parchment-like surface (Fig. 11A). Aneto- infiltrate composed mainly of atypical lymphocytes together derma arising in classic MF lesions is very rare and has only with hemosiderin-containing macrophages and extravasated been described in 2 patients to date.58 erythrocytes. The purpuric lesions progress to the typical The histopathologic findings observed in the 2 patients lesions seen in MF and this variant is more common in were similar to those seen in classic MF, but elastic tissue males.62,63 stains (e.g., orcein and Van Gieson) also showed absence of The greatest diagnostic challenge lies in distinguishing elastic fibers in the dermis (Fig. 11 B-D). Contrasting with purpuric MF from other benign purpuric skin disorders as granulomatous slack skin, elastophagocytosis is an uncom- clinical and on occasions histopathologic findings overlap; a mon focal finding in anetodermic MF.58 putative relationship between chronic pigmented purpuric dermatosis and MF has been proposed.63---65 Hyperpigmented MF Hyperpigmented MF is a very uncommon variant of MF in Pustular MF which hyperpigmented macules and plaques are often the The term pustular MF refers to an extremely rare clini- only clinical manifestation of disease. Hyperpigmented MF is copathologic variant of MF that was initially described by 204 H. Muñoz-González et al. Figure 12 Granulomatous mycosis fungoides. A, Photograph of patch-stage and plaque-stage mycosis fungoides lesions distributed on the trunk and extremities. B, Panoramic view showing perivascular sarcoidal granulomas throughout the dermis. C, Detailed view of a granuloma composed of atypical lymphocytes, histiocytes, and giant multinucleated cells. Ackerman66 as a long-standing vesicular pustular eruption cases, complicating diagnosis in patients without character- that progressively gives way to typical MF plaques. The pus- istic clinical manifestations.45 Some follicular involvement tules can be generalized or confined to the palmoplantar may be occasionally observed (Fig. 12B and C). surfaces.67,68 Granulomatous MF is clinically characterized by patches, Histopathologic examination shows typical MF features, plaques, and tumors similar to those seen in classic MF, such as a band-like infiltrate of atypical lymphocytes, epi- but there may also be alopecia when the scalp is involved dermotropism, and Pautrier microabscesses, in association (Fig. 12A).73 Prognosis seems to be poorer than in classic with subcorneal pustules containing atypical lymphocytes, MF. Granulomatous MF responds poorly to topical treatment, neutrophils, and eosinophils.68 The proportion of neoplas- frequently progresses, and is associated with a high risk of tic and inflammatory cells is variable, but the latter a second lymphoma.73---75 predominate.66 Although granulomatous MF is essentially distinguished from granulomatous slack skin on clinical grounds, Verrucous MF histopathologic examination shows a lower proportion of Verrucous or hyperkeratotic MF, another rare variant of MF, is multinucleated cells, and elastolysis and elastophagocytosis characterized by the presence of localized or disseminated are absent.24,49 verrucous hyperkeratotic lesions that affect acral surfaces and may coexist with typical MF lesions.24,69,70 The differen- Interstitial MF tial diagnosis should include palmoplantar MF confined to Interstitial MF is an uncommon variant of MF and it is these regions. Histopathologic findings include classic MF clinically indistinguishable from classic MF. It is defined features in addition to a perivascular inflammatory infil- by its histopathologic features, which include a predom- trate in the papillary dermis, spongiosis and exocytosis in inantly lymphocytic infiltrate and histiocytes scattered the epidermis, and papillomatosis and hyperkeratosis.71 among collagen bundles in the dermis, mimicking interstitial granuloma annulare or the inflammatory phase of morphea Histopathologic Variants of MF (Fig. 13).76---78 Additional findings include epidermotropism and mucin deposits in the dermis. Pautrier microabscesses Granulomatous MF are uncommon. Interstitial MF is distinguished from gran- Granulomatous MF is a histopathologic variant that must be uloma annulare by its monoclonal lymphocytic population diagnosed by skin biopsy. Findings include perivascular sar- (granuloma annulare has a predominantly histiocytic infil- coidal granulomas throughout the dermis and an infiltrate of trate) and the observation of classic MF features in other atypical lymphocytes, histiocytes, and giant multinucleated lesions, although coexistence of MF and interstitial granu- cells.72 Epidermotropism is observed in approximately 50% of loma annulare has been described.79 Clinicopathologic Variants of Mycosis Fungoides 205 Figure 13 Interstitial mycosis fungoides. A, Panoramic view showing a mild infiltrate in the papillary dermis. B, Higher- magnification view showing the interstitial pattern of the infiltrate. C, D, Detailed view of the predominantly lymphocytic infiltrate among the collagen bundles and other adnexal structures of the dermis. Figure 14 Mycosis fungoides with large-cell transformation. A, Panoramic view of biopsy specimen from the scalp showing the patch-like infiltration of the dermis. B, Detailed view of the neoplastic infiltrate in the hypodermis. C,D, Higher-magnification view showing the large pleomorphic and anaplastic neoplastic cells in the infiltrate. 206 H. Muñoz-González et al. MF With Large-Cell Transformation 7. Girardi M, Heald PW, Wilson LD. The pathogenesis of mycosis Transformation of MF into large T-cell lymphoma is a fungoides. N Engl J Med. 2004;350:1978---88. histopathologic variant of MF in which over 25% of the neo- 8. Massone C, Kodama K, Kerl H, Cerroni L. Histopathologic plastic infiltrate is formed by large, pleomorphic, anaplastic features of early (patch) lesions of mycosis fungoides: A mor- phologic study on 745 biopsy specimens from 427 patients. Am cells and immunoblasts; it is more common in patients with J Surg Pathol. 2005;29:550---60. tumor-stage MF.80 CD30 expression by large cells is variable 9. Pimpinelli N, Olsen EA, Santucci M, Vonderheid E, Haeffner AC, and CD30 negativity has been associated with worse prog- Stevens S, et al. Defining early mycosis fungoides. J Am Acad nosis (Fig. 14).81 Dermatol. 2005;53:1053---63. This histologic variant of MF must be distinguished from 10. Ferrara G, di Blasi A, Zalaudek I, Argenziano G, Cerroni L. other primary cutaneous lymphomas with CD30+ large cells, Regarding the algorithm for the diagnosis of early mycosis fun- such as anaplastic large-cell lymphoma and lymphomatoid goides proposed by the International Society for Cutaneous papulosis. In MF, the percentage of large cells rarely reaches Lymphomas: Suggestions from routine histopathology practice. the 75% necessary to diagnose anaplastic large-cell lym- J Cutan Pathol. 2008;35:549---53. phoma and the characteristic IRF4 translocations seen in the 11. Wood GS. T-cell receptor and immunoglobulin gene rear- rangements in diagnosing skin disease. Arch Dermatol. latter are generally not found in MF.82 The distinction with 2001;137:1503---6. lymphomatoid papulosis must be based on clinical findings, 12. Zhang Y, Wang Y, Yu R, Huang Y, Su M, Xiao C, et al. Molecular such as the absence of spontaneous regression in MF.83 markers of early-stage mycosis fungoides. J Invest Dermatol. Transformation of MF into large-cell lymphoma wors- 2012;132:1698---706. ens prognosis and is associated with terminal stages of the 13. Castano E, Glick S, Wolgast L, Naeem R, Sunkara J, Elston disease.81,82 D, et al. Hypopigmented mycosis fungoides in childhood and adolescence: A long-term retrospective study. J Cutan Pathol. 2013;40:924---34. Ethical Disclosures 14. Boulos S, Vaid R, Aladily TN, Ivan DS, Talpur R, Duvic M. Clinical presentation, immunopathology, and treatment of juvenile- Protection of humans and animals. The authors declare onset mycosis fungoides: A case series of 34 patients. 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