MF is the most frequent subtype of PCL, with an annual incidence of 0.3−0.5 new cases per 100,000 population. It affects adult patients with a 2:1 predilection for men. MF is a monoclonal proliferation of mature memory CD4+/CD45RO+T-helper cells.2

In its initial stages, MF remains localized to the skin for years in the form of erythematous-scaly macules or plaques with persistent infiltration, usually at sites corresponding to covered areas of the skin. In the initial phases (stages IA, IB, IIA), the disease has no impact on survival. In a limited percentage of patients (20%), the disease progresses to more advanced stages, developing solitary or multiple nodules or tumors, with a tendency towards ulceration (stage IIB). These lesions usually coexist simultaneously with macules or plaques and/or show specific lymph node and visceral involvement (stage IV) (Fig. 1A-C). Age greater than 60 years, elevated LDH levels, presence of visceral involvement, and histological transformation to large-cell lymphoma are considered factors for poor prognosis in MF.9–11

Fig. 1.

A, Mycosis fungoides (MF) lesion in macular phase. B, Plaque-type MF lesion. C, Tumor MF. D, Histology of plaque MF with band-like infiltrate of the superficial and medial reticular dermis with large atypical lymphocytes. Epidermotropic processes may be present. E, Ki67 proliferation marker allows detection of large lymphoid cells. F, Diffuse infiltrate throughout the dermis corresponding to a tumor MF lesion. G, Large cells with pleomorphic nuclei from an MF tumor biopsy. H, Proliferation index >50% in a tumor MF lesion.

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Histopathological study of initial macules shows an infiltrate in the superficial dermis, formed of small cerebriform lymphocytes that are often distributed along the basal layer of the epidermis (epidermotropism) with no spongiotic changes. Progression of the lesions to plaques gives rise to a denser band-like infiltrate in the papillary dermis, and stronger epidermotropism (intraepidermal Pautrier microabscesses). The tumors are characterized by dense monomorphic infiltrates of atypical nodular or diffuse lymphocytes, involving the full thickness of the dermis. The presence of large cells (usually CD30+) is frequent and when these account for more than 25% of the infiltrate, large-cell transformation is considered to have occurred (Fig. 1D-H). The usual phenotype is CD2+, CD3+, βF1+, CD4+, CD8–, CD45RO with a loss of mature T-lymphocyte markers (CD7, CD, or CD5). A cytotoxic phenotype (CD8+, TIA1+ or γδ+) in MF is not usually associated with differences in clinical presentation, prognosis, or progression. Clonality study by polymerase chain reaction detects monoclonal T-cell receptor (TCR) reordering in most cases.3

Patients with MF/SS have complex, heterogeneous, nonspecific genomic abnormalities in the genes implicated in T-cell activation, apoptosis, chromatin remodeling, or response to DNA damage, as well as cell cycle regulating genes (TP53, PLCG1, CARD11, STAT5B, NFKB2, IL6, ITPR1, RASA2, TNFRSF10A, FASN, ZEB1, DNMT3A, or KMT2C). Specifically, activation of signaling pathways such as STAT, NOTCH1, or β-catenin (by NF-kB) appear to be key in this process.12–20

Folliculotropic MF (FMF) is a particular clinicopathologic variant characterized by preferential tropism for the hair follicle epithelium. It can be associated with follicular mucinosis. The lesions are usually located on the face, neck, and trunk, and are manifest as grouped follicular papules, cysts, comedones, areas of alopecia, and/or pseudotumoral lesions (Fig. 2A and B). Overall survival at 10 years is approximately 82% compared with 91% for the classic form, and 41% and 90%, respectively, at 15 years. However, recently, the presence of different subgroups of FMF has been proposed: an early or ‘superficial’ form with a small prominent neoplastic component with a prognosis similar to classic MF in its initial stages, and a ‘deep’ variant with a more aggressive course.21,22 Syringotropic MF is the term used for those forms of MF with exclusive or predominant involvement of the eccrine glands. The lesions usually comprise infiltrated, hyperpigmented and anhidrotic plaques and, often, alopecia. Syringotropic MF can develop either in isolation or associated with FMF (adnexotropic MF).

Fig. 2.

A, Papular and comedonal lesions of folliculotropic mycosis fungoides (FMF). B, Histology of an incipient or superficial papular FMF lesion that exhibits lymphoid folliculotropism and follicular mucinosis processes.

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Pagetoid reticulosis (PR) is a localized variant of MF, characterized clinically by one or several hyperkeratotic plaques, generally in distal areas of the limbs, and histopathologically by strong epidermotropism. Neoplastic cells present a CD8+ or CD4+ phenotype and often, they are CD30+. They should be differentiated from other subtypes of aggressive PCTCLs with prominent epidermotropism, as PR follows an indolent clinical course, with localized radiotherapy as the treatment of choice.1

Granulomatous slack skin is a particular and uncommon variant of MF characterized clinically by slow and progressive development of redundant skin in the large folds (axillae, groin). Histologically, a dense infiltrate is observed with granulomatous features, with dense dermal lymphoid infiltrates and abundant multinucleated giant cells with elastophagocytosis and elastolysis. In addition, infiltration of superficial layers is usually observed with atypical lymphoid cells and a variable degree of epidermotropism.1

Traditionally, SS is characterized by erythroderma, generalized swollen lymph nodes, and more than 1000/mm3 (or >10%) atypical circulating mononuclear cells with cerebriform nucleus (Sézary cells). It is observed almost exclusively in elderly adults and has a certain predilection for men. Along with diffuse erythroderma (erythema that affects >80% of body surface) associated with intense pruritus, it is usually accompanied by ectropion, palmoplantar keratoderma, nail dystrophy, and alopecia (Fig. 3). The circulating Sézary cells are CD4+, CD7-, CD26- with a CD4+/CD8+ T-cell ratio >10. Evidence of clonal expansion of CD4+/CD7− ≥40% or CD4+/CD26− ≥30% would also be considered sufficiently strong for diagnosis. Cutaneous histopathological findings in SS are similar to those observed in MF, although epidermotropism is usually weaker. The disease usually follows an aggressive course, and 5-year survival does not exceed 30%–40%.7,10,23

Fig. 3.

Erythroderma in a patient with Sézary syndrome.

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Patients with stage IA-IIA disease should be initially treated with therapies targeting the skin, such as topical corticosteroids or phototherapy (psoralen-UV-A [PUVA] therapy or narrow-band UVB therapy).24,25 Topical cytostatic agents (mechlorehamine or carmustine) can achieve therapeutic responses in more than 50% of patients, although their use is limited by poor tolerance (irrative dermatitis).26 Other topical treatments include gel bexarothen (not reimbursed), resiquimod (unapproved toll-like receptor agonist), and occasionally calcineurin inhibitors (also unapproved) or photodynamic therapy.27,28 In those patients with disseminated infiltrated plaques, or in patients who are refractory to the aforementioned treatments, oral bexarotene29 or interferon-α30 are usually prescribed as monotherapy, or, alternatively, combinations of bexarotene, inferferon-α, or PUVA therapy may be used.24 Total skin electron radiation is an effective therapeutic alternative in some patients with MF in stages IB or IIA (Fig. 4).31–33 In FMF, the best results appear to be achieved with the use of PUVA associated with bexaroten or interferon-α or with total skin electron radiation.34

Fig. 4.

Therapeutic algorithm for mycosis fungoides/Sézary syndrome.

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In patients with single or localized tumors (stage IIB), localized radiotherapy is used, while in the case of multiple lesions, gemcitabine or doxorubicin are used in monotherapy.3,35,36 Other treatments that modify biological response, such as histone deacetylase inhibitors (vorinostat, romidepsin), used both for advanced and early disease, in monotherapy or in combination with other treatments, could be of use, although they are still not approved in the European Union.37 Polychemotherapy regimens (CHOP) are only indicated in patients with lymph node and/or visceral involvement (stage IV) who are refractory to the aforementioned therapies or in the context of treatment prior to hematopoietic stem cell transplantation. Recently, brentuximab vedotin (monoclonal antibody to the CD30 antigen) and mogamulizumab (monoclonal antibody to the CCR4 receptor) have been approved in patients with advanced MF and SS (Fig. 4).38,39

Extracorporeal photopheresis is considered the initial treatment of choice for SS after diagnosis.40 It can be associated with interferon-α, bexarotene, full body radiation, or PUVA therapy. Methotrexate, prednisone, and chlorambucil are classic therapies in SS, although their efficacy is relatively low. In refractory patients, management of advanced SS is not notably different to that of advanced MF, although some drugs such as alemtuzumab (monoclonal antibody to CD52 antigen) and mogamulizumab could have a more favorable efficacy/toxicity profile in patients refractory to SS.41 Mogamulizumab has demonstrated better therapeutic response in the blood compartment (unlike brentuximab, which appears to have better efficacy in the cutaneous compartment)(Fig. 4).23,24,38,39

Finally, in patients with advanced MF/SS, the possibility of hematopoietic stem cell transplantation should be considered.42 Alternatively, such patients could be candidates for clinical trials, given that several molecules are in development aimed at both controlling immune response (anti-PD1 or anti-PDL1 monoclonal antibodies) and enhancing monoclonal antibody-mediated cytotoxicity (KIRDL2).43

Primary cutaneous CD30+ lymphoproliferative disorders are a group of cutaneous lymphoproliferative disorders that have in common expression of the lymphoid CD30 activation antigen by neoplastic cells. The range of entities includes lymphomatoid papulosis (LP) and CD30+ anaplastic large-cell lymphoma (CD30+ALCL). Prognosis is usually good, with mean survival in excess of 90% at 5 years.1

LP is characterized by the recurrent and chronic development of papules or nodules that spontaneously involute, often leaving residual scars. The lesions are usually erythematous papules, with a tendency to ulceration and central necrosis, and of variable size, number and distribution (isolated, grouped, or disseminated lesions) usually located on the trunk and extremities (Fig. 5A). Between 5% and 20% of patients may show an association with another neoplastic process, usually hematologic (Hodgkin lymphoma) or MF.44

Fig. 5.

A, Papules at different stages of development corresponding to lymphomatoid papulosis (LP). B, Dermal infiltrate formed of atypical lymphocytes and rich in eosinophils from a papular LP lesion. C, Large-cell lymphocytes with nuclear pleomorphism in an LP lesion. D, Expression of CD30 antigen in large lymphocytes with an activated appearance in LP.

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LP shows a lymphoid infiltrate of perivascular and interfacial wedge-shaped arrangement in the dermis, occasionally spreading to subcutaneous tissue. Atypical large lymphoid cells, which express CD30 antigen, similar to Reed-Sternberg cells in Hodgkin lymphoma, can be observed in this infiltrate. Likewise, a dense accompanying inflammatory infiltrate can be observed with abundant polymorphonuclear neutrophils and eosinophils. Histopathological findings observed may require differential diagnosis with lichenoid pityriasis or even with arthropod bites. The neoplastic cells express the T-helper phenotype (CD3+, CD4+, CD8−) with the presence of groups of atypical CD30+ large cells (Fig. 5B-D).44

In recent years, different histopathological variants have been reported. Along with the classic type A (histiocytic), type B (similar to MF), or type C (similar to PCTCL-CD30+) forms,44 variants with cytotoxic phenotype (type D) have been described.45 These processes may resemble a primary cutaneous aggressive epidermotropic cytotoxic T-cell lymphoma. Variants with angioinvasive histology (type E),46 which are usually manifest clinically with ulcerous-necrotic lesions, predominantly folliculotropic, granulomatous, forms, etc, have also been described. These variants do not follow a distinct clinical course, although they may present diagnostic difficulties to differentiate from other lymphoproliferative disorders. Genetic mutations specific to LP have not been described, although recently reordering of the DUSP22 gene with IRF4 at the 6p25.3 locus has been reported in a limited number of cases.47

Diagnosis of PL is established according to clinical-pathologic features of the cutaneous lesions and its self-resolving character. Treatment of LP is determined by the extent and characteristics of the lesions. Often, no treatment is required. In cases of extensive, necrotic lesions, or lesions with a tendency to cause scarring, treatment with low-dose oral methotrexate (7.5 to 15 mg/week or even lower doses), phototherapy (UVB or PUVA therapy), or interferon-α can be prescribed. Exceptionally, treatment with brentuximab could be considered.38,44

Primary cutaneous CD30+ anaplastic large-cell lymphoma presents characteristically as a solitary nodule or multiple nodules of variable size in groups or at different anatomical sites; these lesions are fast-growing and with a tendency to ulcerate (Fig. 6A). For staging, the TNM classification for different PCL of the MF/SS group is applied (Table 5). Approximately 10% of patients can develop extracutaneous involvement, generally of locoregional lymph nodes.44

Fig. 6.

A, Primary cutaneous CD30+ anaplastic large-cell lymphoma. B, Diffuse dermal infiltrate of atypical lymphoid cells. C, Atypical lymphoid cells with pleomorphic nuclei. D, Expression of CD30 antigen in most of the cells of the infiltrate.

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Histologically, this process is characterized by diffuse dermal infiltration formed of large atypical lymphoid cells with abundant cytoplasm, rounded-oval nuclei, and prominent nucleoli. These cells have a CD4+/CD45RO+T-cell phenotype with intense expression of CD30 antigen (>75% of neoplastic cells) (Fig. 6B-D). Expression of CD56 or cytotoxic markers is not exceptional (TIA-1, granzyme B) but without any prognostic implications.44

In CD30+PCTCL, t(2;5)(p23;q35) chromosomal translocation is not detected; this finding characterizes nodal origin anaplastic lymphomas. Likewise, expression of its corresponding fusion protein NPM/ALK (anaplastic lymphoma kinase) associated with this translocation is not detected. The EMA antigen is also not expressed and these cells are CD15- unlike those of nodal anaplastic lymphomas and Hodgkin lymphoma. In approximately 25% of cases, DUSP22/IRF4 translocation can be detected.44

This entity usually has a good prognosis, even in those cases with secondary locoregional lymph node involvement, with 5-year survival rates greater than 75% to 90%. Conservative treatment with surgery or radiotherapy is often recommended in solitary lesions, or else methotrexate, interferon, or monochemotherapy in those cases with localized lesions. In the event of extensive multicentric cutaneous involvement, treatment with brentuximab should be considered, and only exceptionally with other more aggressive alternatives (polychemotherapy).44