Mycosis fungoides variants—clinicopathologic features, differential diagnosis, and treatment Rein Willemze, MD, PhD slack skin (GSS) are recognized as distinct variants of MF because ■ Abstract of their distinctive clinicopathologic features, clinical behavior, Mycosis fungoides (MF) is the most common type of and/or prognosis.1,7 In this review, the clinical and histopathologic cutaneous T-cell lymphoma, which typically presents with features, differential diagnosis, and treatment of these 3 variants erythematous patches and plaques, histopathologically are presented. Hypopigmented MF, which is the most common characterized by superficial infiltrates of small to medium- sized atypical epidermotropic T cells. Apart from this variant in childhood and adolescence, and other rare variants are classic type of MF, many clinical and/or histopathologic shortly discussed. variants have been described. Correct diagnosis of these MF variants is important, but may be difficult, because they Folliculotropic MF may mimic a wide variety of inflammatory skin diseases. In FMF is a distinct variant of MF characterized by the presence of this review, clinical and histopathologic characteristics of folliculotropic infiltrates, often with sparing of the interfollicular distinct variants of MF are presented, and their differential diagnosis and therapeutic options are discussed. epidermis and preferential involvement of the head and neck re- gion.1 In large series, FMF accounts for approximately 10% of all Semin Cutan Med Surg 37:11-17 © 2018 Frontline patients with MF.2,3 Most cases show mucinous degeneration of the Medical Communications hair follicles (follicular mucinosis) and were originally designated as MF-associated follicular mucinosis. Similar cases, but without follicular mucinosis, have been reported as pilotropic MF.8 ycosis fungoides (MF) is the most common type of cu- It should be emphasized that FMF is defined by a combination taneous T-cell lymphoma (CTCL) and accounts for ap- of clinical and histopathologic criteria. Infiltration of hair follicle Mproximately 50% of all primary cutaneous lymphomas.1 epithelium by neoplastic T cells can also be observed in other types Patients with classical MF present with patches and plaques that of CTCL, such as CD8-positive aggressive epidermotropic cyto- are preferentially located on the buttocks and other covered sites toxic CTCL (CD8+ AECTCL), lymphomatoid papulosis (LyP), of the trunk and limbs (sun-protected areas). Histopathologically, and cases of classic MF, and is in itself insufficient for a diagnosis these early stages are characterized by superficial band-like or li- of FMF.9,10 chenoid infiltrates of small to medium-sized atypical T cells with cerebriform and sometimes hyperchromatic nuclei, which charac- Clinical features teristically infiltrate into the epidermis (epidermotropism). Most FMF mostly presents in adults but has also been reported in patients have a protracted clinical course over years or even de- children and adolescents.11-16 Men are affected more often than cades. However, a proportion of patients may develop nodules or women. Patients may present with (grouped) follicular papules, tumors and eventually progress to extracutaneous disease.2,3 Clas- follicle-based patches, indurated plaques, or tumors, which pref- sic MF, also called Alibert–Bazin type of MF, is discussed in detail erentially involve and are most pronounced in the head and neck in the article by Lorenzo Cerroni in this same issue. area (Figure 1).11-14,17 Other clinical manifestations are acneiform Apart from classical MF, many clinical and/or histopathologic lesions (comedones, cysts) and keratosis pilaris-like lesions that variants of MF mimicking a wide variety of inflammatory skin dis- are mainly localized on trunk and extremities.18 The skin lesions eases have been described.4-6 These include, among others, eryth- are often associated with alopecia. Children most commonly pres- rodermic, hypopigmented, hyperpigmented, bullous/vesicular, ent with hypopigmented folicle-based patches with associated alo- poikilodermatous, folliculotropic, syringotropic, granulomatous, pecia.15 Infiltrated plaques in the eyebrow region with concurrent and even invisible MF. Most variants have a clinical behavior simi- alopecia are a common and highly characteristic finding. Pruritus lar to that of classic MF, and in recent classifications they are there- is often severe and may represent a reliable parameter of disease fore not classified separately. In the WHO European Organization activity. Secondary bacterial infections are frequently observed.17 of Research and Treatment of Cancer (WHO-EORTC) classifica- In rare cases, FMF may present with a solitary skin lesion (solitary tion and in the 2017 revision of the WHO classification, only fol- or unilesional FMF) or with erythroderma.19-21 liculotropic MF (FMF), pagetoid reticulosis, and granulomatous Histopathology and immunophenotype Histopathologically, FMF is characterized by the presence of peri- Department of Dermatology, Leiden University Medical Center, Leiden, The follicular to diffuse infiltrates with variable infiltration of the fol- Netherlands. Disclosures: Dr Willemze has nothing to disclose. licular epithelium by small, medium-sized, or sometimes large T Correspondence: Rein Willemze, MD, PhD; [email protected]; wil- cells with cerebriform and hyperchromatic nuclei (Figure 2).11-14,17 [email protected] Many cases show mucinous degeneration of the follicular epithe- 1085-5629/13$-see front matter © 2018 Frontline Medical Communications Vol 37, March 2018, Seminars in Cutaneous Medicine and Surgery 11 DOI: 10.12788/j.sder.2018.004 ■ ■ ■ Mycosis fungoides variants—clinicopathologic features, differential diagnosis, and treatment A B C D ■ FIGURE 1. Clinical manifestations of FMF. (A) Infiltrated plaque with alopecia and cystic lesions above left eye; (B) grouped follicular papules on right arm; (C) infiltrated plaque with hyperkeratotic papules on left cheek; (D) erythematous tumor and many cystic lesions. FMF, folliculotropic mycosis fungoides. lium (follicular mucinosis), which can be visualized by Alcian blue presence of more than 25% of blast cells or the presence of clusters or colloidal iron staining, but cases without follicular mucinosis of blast cells, has been reported in more than 20% of FMF cases have been described as well.8 Infiltration of the follicular epithe- and is more common than in classical MF.12,14,17 lium may be accompanied by infiltration of the eccrine sweat In virtually all cases, the neoplastic cells in FMF have a CD3+/ glands (syringotropism), a combination that is often referred to as CD4+/CD8− T-cell phenotype as in classic MF.22 Admixed blast adnexotropic MF.21-23 However, concurrent infiltration of the in- cells are often CD30 positive. Most cases show clonal T-cell re- terfollicular epidermis (epidermotropism) characteristic of early- ceptor gene rearrangements.22 stage classic MF is uncommon. In early-stage lesions, clinically characterized by follicle-based patches or acneiform or keratosis Differential diagnosis pilaris-like lesions, the perifollicular infiltrates are generally sparse The distinctive clinical and histopathologic features should facilitate and contain, apart from atypical T cells, variable numbers of small an early and correct diagnosis. However, because of the preferential reactive T cells, histiocytes, and occasionally eosinophils. With involvement of the head and neck area, the absence of patches and progression of the skin lesions to more infiltrated plaques or tu- plaques on the trunk and buttocks, and particularly because of the mors, the dermal infiltrates become more diffuse and may contain absence of epidermotropic atypical T cells, the diagnosis of MF or increasing numbers of blast cells. There is often a considerable CTCL is often not considered and is misinterpreted as seborrheic admixture with eosinophils and, in particular, in cases with sec- dermatitis, atopic dermatitis, or rosacea. Clinicopathologic cor- ondary bacterial infection, plasma cells. In some cases, clusters of relation is also required to differentiate FMF from other types of small B cells may be present. In cases with destruction of the hair CTCL. Because the perifollicular infiltrates often contain scattered follicle epithelium, a granulomatous reaction can be observed.22 In or clusters of CD30-positive blast cells, histopathologic differentia- cases with diffuse dermal infiltrates with partial or even complete tion between FMF and primary cutaneous CD30-positive lymphop- destruction of the epithelial structures, differentiation between roliferations (cutaneous anaplastic large-cell lymphoma; LyP) may FMF and other types of CTCL may be challenging. In such cases, be challenging. In case hair follicles have been destroyed or are com- staining with monoclonal antibodies against keratin may be useful pletely obscured by diffuse dermal infiltrates, it may be difficult or to visualize infiltration of residual hair follicles and sweat glands even impossible to differentiate between FMF and primary cutane- by neoplastic T cells.21 Large-cell transformation, defined by the ous peripheral T-cell lymphoma, unspecified. In such cases, addi- 12 Seminars in Cutaneous Medicine and Surgery, Vol 37, March 2018 Willemze tional biopsies and clinical follow-up are needed to make a definite and abundant, vacuolated cytoplasm. The superficial dermis may diagnosis.21 The relationship between FMF and the so-called benign