Cutaneous T Cell Lymphoma (Chapter 120)

CTCLs represent approximately what % of all primary cutaneous lymphomas?

List cutaneous T cell lymphomas with Indolent clinical behavior
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Terms in this set (37)
CTCLs represent approximately 75-80% of all
primary cutaneous lymphomas, whereas primary cutaneous B-cell lymphomas (CBCLs) account for approximately 20-25%

Indolent clinical behavior

Mycosis fungoides (MF) 54

Mycosis fungoides variants
• Folliculotropic MF 6
• Pagetoid reticulosis 1
• Granulomatous slack skin <1

Primary cutaneous CD30-positive lymphoproliferative disorders
• Primary cutaneous anaplastic large cell lymphoma (C-ALCL) 10
• Lymphomatoid papulosis (LyP) 16

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL)

Primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disorder¶

Primary cutaneous acral CD8-positive T-cell lymphoma¶
The first step in the evaluation of a patient suspected of having CTCL is to decide if it represents a lymphoma or a benign condition. Skin biopsies - preferably deep punch biopsies 4-6 mm wide or an excisional or incisional biopsy from the most representative skin lesions - should be performed. In the US, broad saucerizations are also done for suspected patch/plaque stage MF.
Since prior treatment with topical corticosteroids or PUVA may change the original histology profoundly, biopsies from untreated skin lesions are preferred. Even if an adequate biopsy specimen is obtained, a definite diagnosis is not always possible. First, several types of CTCL, such as MF, are often preceded for years by skin lesions that are neither clinically nor histologically diagnostic. The gradual progression from this prediagnostic phase to overt lymphoma explains why it has always been so difficult to reach a consensus on the minimal histologic criteria needed for an unequivocal diagnosis of MF6. Because of the indolent clinical behavior of the disease in such patients, a conservative approach is justified. In most cases, repeated biopsies, when appropriate, will ultimately result in the correct diagnosis.
Secondly, atypical T-cell infiltrates are found not only in CTCL but also in reactive conditions, e.g. lymphomatoid drug eruptions (pseudo-T-cell lymphomas)7. Therefore, a definite diagnosis should always be based on a combination of clinical, histologic and, in most cases, immunophenotypical criteria, and it may be supplemented with the results of gene rearrangement analysis
Immunohistochemical studies on paraffin or frozen sections using antibodies reactive with cell-surface or cytoplasmic molecules are extremely important in the diagnosis and classification of cutaneous lymphomas. Nowadays, antigen retrieval techniques allow immunophenotyping on formalin-fixed, paraffin-embedded tissue sections, eliminating the need for frozen sections. By using a panel of such antibodies (see Ch. 0), distinction can be made between neoplasms of T-cell, B-cell, NK-cell, and myeloid or monocytic origin. Within the group of CTCLs, such studies have contributed to the delineation of new subtypes and provided important diagnostic and prognostic criteria.
With respect to the diagnosis of CTCL, demonstration of an aberrant phenotype, i.e. loss of one or more T-cell-associated antigens, such as CD2, CD3, CD4 or CD5, by the neoplastic T cells, can be considered as an important additional criterion in establishing a definite diagnosis of CTCL8. However, loss of CD7 expression, which may be caused by SkinINchronic T-cell stimulation and is commonly observed in benign dermatoses, is not a reliable marker.
T-cell receptor gene rearrangement analysis
T-cell receptor (TCR) gene rearrangement analysis, utilizing a standardized assay (e.g. BIOMED-2), may provide useful information for the diagnosis and staging of malignant lymphomas9. However, caution is warranted in interpreting the results of such analyses. Clonal T-cell populations have been detected not only in skin lesions, lymph nodes, and peripheral blood of patients with CTCL and in cases of chronic dermatitis preceding MF ("clonal dermatitis"; see Ch. 9), but also in skin lesions of patients with apparently benign conditions, such as pityriasis lichenoides et varioliformis acuta, lichen planus, lichen sclerosus and some pseudolymphomas10.
Demonstration of clonal T-cell populations can therefore not be used as an absolute criterion of malignancy, but should always be considered in conjunction with clinical and histologic features, which together remain the "gold standard". If the clinical and histologic findings are not consistent, and an aberrant phenotype is not detected, a definite diagnosis of CTCL should not be made. In the future, high-throughput TCR sequencing may be used to enhance detection of T-cell clones in patients with CTCL and for distinguishing CTCL from benign inflammatory diseases
Step one: Based on a combination of clinical, histologic and immunophenotypical criteria, distinction is first made between classic MF, MF variants, and SS on the one hand and CTCL other than these conditions on the other. The rationale for this first step is that dermatologists are familiar with the former set of
conditions, which comprise approximately 65% of CTCLs, and these lymphomas require a different clinical approach in terms of staging and therapy compared to the other forms of CTCL.

Step two: The second category to be considered is the group of primary cutaneous CD30-positive lymphoproliferative disorders. It implies that evaluation of skin biopsies from patients with (suspected) CTCL should always include CD30 immunostaining.
This group includes cases of cutaneous ALCL (C-ALCL) and LyP, which together represent the second most common group of CTCL (see Table 120.1). Patients within this spectrum of disease generally have an excellent prognosis, and most individuals can be managed easily by dermatologists.
Step three: With the first two steps, approximately 90% of CTCL will be classified correctly. The remaining group (10% of patients) contains rare types of CTCL, including subcutaneous panniculitislike T-cell lymphoma (SPTCL), extranodal NK/T-cell lymphoma, nasal type, and the broad group of primary cutaneous peripheral T-cell lymphoma (PTCL), not otherwise specified (NOS). From the latter group, primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disorder, and primary cutaneous acral CD8-positive T-cell lymphoma have been separated out as provisional entities (see Table 120.1).

In the WHO-EORTC classification, the term PTCL, NOS is maintained for remaining cases that do not fit into any of the provisional entities.
Apart from SPTCL, primary cutaneous CD4-positive small/ medium T-cell lymphoproliferative disorder, and primary cutaneous acral CD8-positive T-cell lymphoma, lymphomas included in this third category have an aggressive clinical course, and they should be treated by, or in close collaboration with, a hemato-oncologist. It should be emphasized that because of overlapping clinicopathologic features and highly aberrant
phenotypes, distinction between these different types of aggressive CTCL is sometimes very difficult. Distinction between primary and secondary cutaneous involvement is less important than in other types of cutaneous lymphoma in that patients presenting
with only skin lesions generally develop extracutaneous disease within a short period of time and have a poor prognosis as well.
Apart from CTCL, a term preferably used only for primary CTCL, systemic T-cell lymphomas frequently present or relapse in the skin. Adequate staging procedures are required to differentiate between CTCL and these systemic lymphomas secondarily involving the skin. The extent of staging procedures is dependent on the type of (suspected) CTCL, and, in the case of classic MF, on the clinical stage of the disease12. In cases of early patch/plaque stage MF, unequivocal cases of LyP, and probably pagetoid reticulosis as well, staging procedures are generally not worthwhile. In cases of suspected SS, adequate staging with special emphasis on assessment of peripheral blood involvement by cytology, immunophenotyping (flow cytometry), and TCR gene rearrangement analysis is essential. In all other types of CTCL, routine hematologic staging, including complete and differential blood cell counts, a serum chemistry panel, computed tomographic (CT) scans and/or positron emission tomography (PET) of the chest and abdomen, and bone marrow sampling, are required
Mycosis fungoides (MF) represents the most common type of CTCL and accounts for ~50% of all primary cutaneous lymphomas (see Table 120.1). The term MF should be restricted to the classic "Alibert-Bazin" type characterized by the typical evolution of patches, plaques and tumors, or for clinicopathologic variants showing a similar clinical course.

MF has an incidence of about 0.4 per 100 000 inhabitants per year in the US14. MF typically affects older adults (median age at diagnosis: 55-60 years), but it may occur in children and adolescents as well. Men are affected more often than women, with a male-to-female ratio of 1.6-2.0 : 1.

The etiology and the pathogenetic mechanisms involved in the development and stepwise progression of MF are largely unknown. Genetic, environmental, and immunologic factors have all been considered.

Genetic factors
Lymphomagenesis is considered to be a multifactorial process, in which a stepwise accumulation of genetic abnormalities may result in clonal proliferation, malignant transformation and, ultimately, progressive and widely disseminated disease. Although the successive clinical steps of tumor progression were described more than a century ago, the molecular events underlying the different steps of tumor progression have not been identified. Gene expression studies of early stage MF revealed overexpression of TOX, which may turn out to be a useful diagnostic marker15,15a. Several studies on tumor stage MF, using array-based comparative genomic hybridization, reported the same recurrent genetic aberrations including gains of chromosome 7p22-21 (45%), 7q21-22 (55%), 8q24 (35%) and 17q21 (40%) and losses of 9p21.3 (40%) and 13q14 (30%)16-18. Loss of 9p21.3, which harbors the CDKN2A, CDKN2B and MTAP tumor suppressor genes, has been associated with a shorter survival in patients with tumor stage MF16,17,19. In addition, constitutive activation of the NF-κB pathway in MF has been observed and may be explained in part by downregulation of NFKBIZ, an inhibitor of this pathway20,21. Whole-genome DNA sequencing has also implicated NF-κB signaling in CTCL pathogenesis22. Of note, somatic copy variants comprised 92% of driver mutations.
Environmental factors
Persistent antigenic stimulation has been demonstrated to play a crucial role in the development of various malignant lymphomas, including mucosa-associated lymphoid tissue (MALT) lymphomas (Helicobacter pylori infection), CBCL (Borrelia burgdorferi infection), and enteropathy-type T-cell lymphoma (celiac disease). In MF, persistent antigenic stimulation has also been proposed as an initial event, but the nature of the antigen(s) involved is unknown. Large case-control studies have suggested a relationship with industrial or environmental exposures, but their role in the development of MF remains controversial23. Whereas the etiologic roles of human T-cell leukemia virus 1 (human T-cell lymphotropic virus 1; HTLV-1) in adult T-cell leukemia/ lymphoma and EBV in nasal NK/T-cell lymphoma have been firmly established, conclusive evidence for a primary etiologic role of these viruses in MF is lacking24.
Immunologic factors
CD8+ cytotoxic T cells (CTL) are thought to play a crucial role in the antitumor response in MF. A relationship between high percentages of CD8+ CTL in the dermal infiltrates and improved survival has been described25. These CD8+ T cells exert their antitumor effect both by a direct cytotoxic effect and by the production of cytokines, particularly interferon (IFN)-γ. They can mediate tumor cell lysis via exocytosis of cytotoxic granules containing perforin, granzymes and T-cell-restricted intracellular antigen (TIA-1), and by expression of Fas ligand (FasL), which interacts with Fas (CD95; APO-1) on the neoplastic T cells23. Both pathways ultimately lead to activation of caspase 3 and tumor cell death. Loss of Fas expression or function by the neoplastic T cells is one of the many mechanisms by which tumor cells can escape from an effective antitumor response26.
The neoplastic T cells in SS and tumor stage MF are derived from CD4+ T cells with a Th2 cytokine profile (production of IL-4, IL-5 and IL-10), whereas the cytotoxic T cells are the main producers of IFN-γ, which plays an important role in augmenting T-cell- and NK-cell-mediated killing. In accordance with this concept, a gradual shift from a predominantly type 1 cytokine profile in MF plaques to a predominantly type 2 cytokine profile in MF tumors has been suggested. Increased levels of Th2 cytokines may impair the Th1 cell-mediated antitumor response and contribute to the immunosuppression seen in patients with advanced MF
Clinical FeaturesClinical features Characteristically, patients with classic MF progress from patch stage to plaque stage and finally to tumor stage disease, and they have a protracted clinical course over years or even decades. Before a definite diagnosis is made, patients generally have many years of nonspecific eczematous or psoriasiform skin lesions and non-diagnostic biopsies. The median duration from onset of skin lesions to the diagnosis of MF is 4-6 years, but it may vary from several months to more than five decades28,29. Early patch stage MF is characterized by the presence of variably sized erythematous, finely scaling lesions, which may be mildly pruritic (Fig. 120.2A). These early lesions may show variable degrees of atrophy, and a poikilodermatous variant consisting of patches with mottled hyper- and hypopigmentation, atrophy, and telangiectasia has been described (formerly called poikiloderma vasculare atrophicans). Generalized hypopigmented lesions may be observed in patients with darkly pigmented skin (Fig. 120.3), and this is also a common presentation of juvenile-onset MF. The initial skin lesions have a predilection for the buttocks and other covered sites of the trunk and limbs. With progression, more infiltrated reddish-brown, scaling plaques develop, which gradually enlarge and may have an annular, polycyclic or typical horseshoe-shaped configuration (Fig. 120.4A). It should be stressed that many patients never progress beyond the plaque stage of the disease. However, a minority (~10%) of patients may develop nodules or tumors. These patients with tumor stage MF characteristically show a combination of patches, plaques, and tumors (Fig. 120.5A); the latter often show ulceration. If only skin tumors are present without preceding or concurrent patches or plaques, a diagnosis of MF is highly unlikely and another type of CTCL should be considered. The risk of developing extracutaneous disease correlates with the extent and type of skin lesions. It is exceedingly rare in patients with limited patch/plaque stage disease, relatively uncommon in patients with generalized plaques, and most likely in patients with skin tumors or erythroderma28,29. Extracutaneous dissemination, almost without exception, first involves the regional lymph nodes draining areas of extensive skin involvement. Visceral involvement may develop subsequently and can involve any organ. The bone marrow is rarely involved.Pathology ImmunophenotypePathology Early patch lesions in MF show superficial band-like or lichenoid infiltrates, consisting primarily of lymphocytes. Atypical cells, with small to medium-sized, highly convoluted (cerebriform) and sometimes hyperchromatic nuclei, are few in number and are mostly confined to the epidermis (epidermotropism). These lymphocytes characteristically colonize the basal layer of the epidermis as single cells surrounded by vacuolated halos, often in a linear configuration (Fig. 120.2B)8,30. In plaques, epidermotropism is generally more pronounced (Fig. 120.4B). The presence of intraepidermal nests of atypical cells (referred to as Pautrier microabscesses, although the initial description was by Darier) is a highly characteristic feature, but is observed in only a minority of cases. The epidermis may show acanthosis and elongated rete ridges, but spongiosis is generally mild or absent. The dermal infiltrates are also more pronounced, and they may contain a higher number of atypical cells with cerebriform nuclei and occasional blast cells, as well as admixed eosinophils and plasma cells. Rarely, a predominantly interstitial infiltrate that resembles granuloma annulare or morphea is observed (interstitial MF)30a. With progression to tumor stage MF, the dermal infiltrates can involve the entire dermis and extend into the subcutaneous tissue. Epidermotropism may no longer be present. The tumor cells increase in number and size, showing variable proportions of small, medium-sized or large cells with cerebriform nuclei, blast cells with prominent nuclei, and intermediate forms (Fig. 120.5B). Large cell transformation, defined by the presence of CD30-negative or CD30-positive large cells exceeding 25% of the infiltrate or forming microscopic nodules, may occur and is generally associated with a poor prognosis. However, within this group, CD30-positive patients have a much better prognosis than CD30-negative patients31. Immunophenotype The neoplastic cells in MF have a mature CD3+, CD4+, CD45RO+, CD8− memory T-cell phenotype. In a minority of patients with otherwise classic MF, a CD3+, CD4−, CD8+ mature T-cell phenotype or more rarely a γ/δ T-cell phenotype (βF1−, TCRγ+, CD3+, CD4−, CD8+) may be seen32,33. Immunophenotyping may demonstrate (partial) loss of T-cell antigens in plaque or tumor stage MF, but rarely in early patch lesions, and is therefore of little help in early diagnosisStagingT (skin) T1 Limited patch/plaque (involving <10% of total skin surface) T2 Generalized patch/plaque (involving ≥10% of total skin surface) T3 Tumor(s) T4 Erythroderma N (lymph node) N0 No enlarged lymph nodes N1 Enlarged lymph nodes, histologically uninvolved N2 Enlarged lymph nodes, histologically involved (nodal architecture uneffaced) N3 Enlarged lymph nodes, histologically involved (nodal architecture [partially] effaced) M (viscera) M0 No visceral involvement M1 Visceral involvement stageIAT1N0M0B0-1IBT2N0M0B0-1IIAT1-2N1-2M0B0-1IIBT3N0-1M0B0-1IIIT4N0-2M0B0-1IVA1T1-4N0-2M0B2IVA2T1-4N3M0B0-2IVBT1-4N0-3M1B0-2More stagingStaging systems and staging procedures Staging patients with MF and SS is important, since it determines management and treatment and has prognostic significance. In 2007, a revised clinical staging system for MF and SS was proposed, which is based on the TNM (tumor-node-metastasis) classification system and takes into account the type and extent of skin lesions (T1-4) as well as the presence or absence of nodal (N0-3), visceral (M0-1), and peripheral blood involvement (B0-2) (Tables 120.3 & 120.4)12. Evaluation of patients suspected of having MF should include a thorough physical examination with special attention to the type and extent of skin lesions and the presence of palpable lymph nodes, as well as skin biopsies, complete blood counts, and serum chemistries. Enlarged lymph nodes should be biopsied. Histologically, distinction can be made between lymph nodes showing dermatopathic lymphadenopathy without involvement by MF (N1), dermatopathic lymphadenopathy with early MF involvement (N2), and lymph nodes showing effacementof the normal lymph node architecture by neoplastic T cells (N3). The prognostic significance of such a subdivision has been well established. No further examinations are recommended for patients with stage IA-B disease. CT scans of the chest and abdomen are recommended in patients in whom extracutaneous disease is suspected, but they are less useful in patients with limited patches and/or plaques without lymphadenopathy. Examination of other organs, including the bone marrow, should only be performed if clinically indicated.TreatmentTreatment The choice of an initial treatment in MF depends on the stage of the disease and the general condition and age of the patient34,35. Given the chronic and recurrent nature of MF, treatment should be aimed at improving symptoms while limiting toxicity. Following the traditional "stage-based" approach, skin-directed therapies are preferred in the early stages of MF (stages IA-IIA) and even in patients with limited tumor stage MF (IIB) (Table 120.5). These skin-directed therapies include topical or intralesional corticosteroids, topical cytotoxic agents (e.g. mechlorethamine [nitrogen mustard]), phototherapy, and radiotherapy. The efficacy of skin-directed therapies in MF is explained by the preferential localization of the neoplastic skin-homing T cells to the epidermis and superficial dermis. Systemic multi-agent chemotherapy is not useful in these early stages, since it does not improve survival and is associated with considerable morbidity. In patients with refractory or progressive skin disease, skin-directed therapies can be combined with IFN-α or systemic retinoids. Alternatively, novel agents such as denileukin diftitox or histone deacetylase inhibitors (HDACi) such as vorinostat and romidepsin can be used, before systemic chemotherapy is considered. Both HDACi and denileukin diftitox have been approved in the US for patients with relapsed and refractory CTCL, but have not been registered for CTCL in Europe. In general, systemic chemotherapy is only indicated in advanced stages when there is nodal or visceral involvement or in patients with rapidly progressive tumors unresponsive to less aggressive therapies.Skin Directed TherapiesSkin-directed therapies Topical corticosteroids In many MF patients with only patches and thin plaques, application of topical corticosteroids is effective in controlling disease activity. In patients with limited patch/plaque stage disease (mainly patches), complete remissions in up to 60% of patients have been reported36. In more advanced stages, they continue to be an important adjuvant therapy. Topical chemotherapy Topical application of mechlorethamine has proven to be an effective treatment for early stage MF. Mechlorethamine, either dissolved in water or compounded in an ointment- or gel-based preparation (see Ch. 129), results in complete remissions in approximately 60-80% of patients with stage IA-B disease36. Most patients with early MF remain clear on maintenance therapy. Side effects include skin irritation, allergic contact dermatitis, and an increased risk for the development of skin cancer related to long-term use. Radiotherapy Total skin electron beam irradiation (TSEB) with an energy of 4-6 MeV is a highly effective treatment in patients with skin-limited MF (see Ch. 139)37. The total dose is generally 36 Gy administered in fractions of 1.5-2 Gy over an 8-10-week period. Recently, lower total doses (10-12 Gy) have been employed, with the advantages of a shorter duration of treatment, fewer side effects, and opportunity for re-treatment38. TSEB is most effective in patients with stage IA-B disease, with complete response rates of >80%. However, in most centers, such patients are treated with phototherapy or topical chemotherapy. TSEB is particularly useful in patients with tumor stage MF, where complete response rates of ~40% have been reported. Side effects are generally mild and include erythema, scaling, and temporary loss of hair, nails and sweat gland function. Local radiotherapy with X-ray or preferably electron beam may be considered for single tumors in patients with plaque stage disease, either in combination with other modalities (e.g. PUVA) as an alternative for TSEB, or for new tumors following TSEB. A dose of ≥8 Gy suffices39. In patients with unilesional MF, local radiotherapy may be curative. Phototherapy Several types of phototherapy can be used in the treatment of MF (Ch. 134). These include PUVA therapy, broadband and narrowband UVB therapy, and, more recently, UVA1 therapy. Extracorporeal photopheresis (ECP) may be effective in patients with erythrodermic MF (see the section on Sézary syndrome). PUVA treatment has become a standard therapy for the early stages of MF36. In patients with stages IA-IIA, complete response rates of 80-90% have been reported. In many centers, maintenance PUVA therapy (every 2 to 4 weeks) is given to prolong remission. Although sustained complete remissions have been reported, most patients will relapse after cessation of PUVA therapy or during maintenance treatment. Recurrent or persistent lesions particularly favor UV-shielded areas, such as the inner thighs and the gluteal cleft. In tumor stage MF, PUVA therapy alone is unlikely to result in complete responses, but favorable results may be achieved when combined with IFN-α, systemic retinoids or radiotherapy. In patients with only patches, narrowband UVB therapy (311 nm) is increasingly being used as a safe and effective alternative to PUVA therapy with similar efficacy36.Systemic TherapiesSystemic therapies (other than chemotherapy) Interferons The most commonly prescribed biological response modifier is interferon-alpha (IFN-α). In most centers, IFN-α is administered subcutaneously in doses of 3 to 9 million units three times a week. Side effects are generally mild and reversible, and they include flu-like symptoms, hair loss, nausea, depression, and bone marrow suppression. The overall response rate of IFN-α, when used as a single agent, is ~50%, with 17% representing complete remissions36,40. The combination of PUVA and IFN-α appears to produce higher response rates than PUVA alone, and this combination may also be considered in patients with early tumor stage disease, when PUVA therapy alone is insufficient. Retinoids When used as a single agent, the overall and complete response rates of several first- and second-generation oral retinoids (isotretinoin, acitretin) and a novel RXR-selective retinoid (bexarotene) are roughly similar to those of IFN-α. A combination of retinoids (including bexarotene) plus PUVA (RePUVA) produces response rates similar to those of PUVA alone, although patients treated with RePUVA require fewer treatments and a lower cumulative UVA dose41. In many centers, bexarotene has replaced the earlier-generation retinoids, but comparative studies have never been performed. In patients with patches or thin plaques, topical retinoids (bexarotene, tazarotene, alitretinoin) may be considered, but skin irritation is a limiting factor36.More Systemic TherapiesDenileukin diftitox Denileukin diftitox is a fusion protein, in which diphtheria toxin is linked to IL-2. It binds to the high-affinity IL-2 receptor expressed by the neoplastic T cells in MF, and internalization of the toxin results in inhibition of protein synthesis and cell death. Overall and complete clinical response rates are ~30% and 10%, respectively35,36. Denileukin diftitox can have substantial side effects, including capillary leak syndrome, fever, and fluid retention. However, at the time of writing, it is not commercially available. Histone deacetylase inhibitors HDACi, such as vorinostat and romidepsin, represent a novel class of drugs used in cancer therapy. Inhibition of the enzyme HDAC affects the expression of many genes (and their protein products) that are involved in cellular proliferation, differentiation, migration and apoptosis. Recent studies of both vorinostat and romidepsin report overall response rates of ~35% in patients with MF and SS, but complete responses are rare35,36. The most common side effects are fatigue, gastrointestinal symptoms, and reversible thrombocytopenia. It remains to be determined which patients are most likely to benefit from this therapy.Systemic chemotherapySystemic chemotherapy Systemic multi-agent chemotherapy should only be used in patients with unequivocal lymph node or visceral involvement, or in patients with progressive skin tumors that have failed to respond to other therapies. In many centers, the standard treatment in such cases is the administration of six cycles of CHOP (cyclophosphamide, hydroxydaunomycin [doxorubicin], Oncovin® [vincristine] and prednisone). With this and other combination regimens, high response rates can be achieved for extracutaneous involvement, but the responses are generally short-lived. Moreover, concurrent patches and plaques are often less responsive, and may require additional treatment with PUVA or mechlorethamine. Recent studies utilizing pentostatin, gemcitabine, and liposomal doxorubicin have demonstrated high overall response rates in patients with advanced MF, but controlled studies are still lacking42,43. In young patients with refractory and/or progressive MF and SS, an allogeneic hematopoietic stem cell transplantation may be considered. Using non-myeloablative reduced-intensity conditioning regimens, durable responses have been reported, but the optimal conditioning regimen and optimal timing for the transplant are still a matter of debate44,45,45a. Results with autologous hematopoietic stem cell transplantation in MF and SS have been disappointing44, suggesting the need for a graft-versus-tumor response. Prognosis The prognosis of patients with MF is dependent on the stage, and in particular the type and extent of skin lesions and the presence of extracutaneous disease28,29. Patients with limited patch/plaque stage MF have a similar long-term life expectancy as an age-, sex-, and race-matched control population. The disease-related 10-year survival is 96% for stage IA, 77-83% for stage IB, 42% for stage IIB, but only 20% for stage IV29,46. Patients usually die of systemic involvement or infections.Folliculotropic MFFolliculotropic MF Definition Folliculotropic MF is a distinct variant of MF characterized by the presence of folliculotropic infiltrates, often with sparing of the epidermis and preferential involvement of the head and neck region. Most cases show mucinous degeneration of the hair follicles (follicular mucinosis; Ch. 46) and are traditionally designated as MF-associated follicular mucinosis. Similar cases, but without follicular mucinosis, have been reported as folliculocentric or pilotropic MF. From a biologic point of view, the most relevant feature (irrespective of the presence or absence of follicular mucinosis) is the deep, follicular and perifollicular localization of the neoplastic infiltrates, which makes them less accessible to skin-directed therapies. For both groups, the term folliculotropic MF is therefore preferred3. Epidemiology This variant is found in approximately 10% of MF patients29,46. It occurs mostly in adults, but may occasionally affect children and adolescents. Men are affected more often than women. Clinical features Patients may present with (grouped) follicular papules, acneiform lesions, indurated plaques and sometimes tumors, which preferentially involve and are most pronounced in the head and neck area (see Fig. 36.16). The skin lesions are often associated with alopecia, and sometimes with mucinorrhea. Infiltrated plaques in the eyebrow region with concurrent alopecia are a common and highly characteristic finding (Fig. 120.6A). Pruritus is often more severe than in classic MF and may represent a reliable parameter of disease activity. Secondary bacterial infections are frequently observed. Treatment Because of the perifollicular localization of the dermal infiltrates, folliculotropic MF is often less responsive to skin-directed therapies, such as PUVA and topical mechlorethamine, than is classic plaque stage MF. In the case of unresponsive disease, a combination of PUVA with either IFN-α or retinoids, local radiotherapy or TSEB can be used, although sustained complete remissions are rarely achievedPagetoid ReticulosisPagetoid Reticulosis Definition This is a rare variant of MF, characterized by the presence of localized patches or plaques with an intraepidermal proliferation of neoplastic T cells. The term pagetoid reticulosis should only be used for the localized type (Woringer-Kolopp type) and not for the disseminated type (Ketron-Goodman type). Nowadays, patients with generalized disease would most likely be classified as having primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, primary cutaneous gamma/delta T-cell lymphoma, or tumor stage MF3. Epidemiology Pagetoid reticulosis is extremely rare, and it accounts for fewer than 1% of CTCL cases. It mostly affects adults. Clinical features Patients present with a solitary psoriasiform or hyperkeratotic patch or plaque, which is usually localized to an extremity and slowly progressive (Fig. 120.7A). In contrast to classic MF, extracutaneous dissemination or disease-related deaths have not been reported. Pathology The typical histologic picture consists of a hyperplastic epidermis with marked infiltration by large atypical pagetoid cells, arranged singly or in nests or clusters (Fig. 120.7B). The atypical cells have medium-sized or large, sometimes hyperchromatic and cerebriform nuclei and abundant, vacuolated cytoplasm. The superficial dermis may have an infiltrate of mostly small lymphocytes, but rarely contains neoplastic T cells. Immunophenotype The neoplastic T cells may show either a CD3+, CD4+, CD8− or a CD3+, CD4−, CD8+ phenotype. CD30 is often expressed49. Differential diagnosis Pagetoid reticulosis should be differentiated from other types of epidermotropic CTCL, such as MF, LyP type B, LyP type D, and primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (see Table 120.2). Useful criteria for pagetoid reticulosis include the characteristic clinical presentation and the often strictly epidermal localization of the neoplastic T cells. Treatment The preferred mode of treatment is radiotherapy or surgical excision.Granulomatous Slack SkinGranulomatous Slack Skin Definition This is an extraordinarily rare type of CTCL characterized by the slow development of folds of lax skin and a granulomatous infiltrate with clonal T cells50. Epidemiology It is an extremely rare type of CTCL, with ~60 cases reported. It typically affects adolescents and adults, and mostly occurs in men. Clinical features This condition is characterized by circumscribed areas of pendulous lax skin with a predilection for the axillae and groin (Fig. 120.8A). In approximately one-third of the reported patients, an association with Hodgkin lymphoma was observed. Most patients have an indolent clinical course. Pathology Fully developed lesions show dense granulomatous dermal infiltrates containing atypical T cells with cerebriform nuclei, macrophages and often many multinucleated giant cells, as well as destruction of elastic tissue and elastophagocytosis by the multinucleated cells (Fig. 120.8B). The epidermis may be infiltrated by small atypical T cells with cerebriform nuclei, as in classic MF. The atypical T cells have a CD3+, CD4+, CD8− phenotype. A large study noted overlapping histologic features between granulomatous slack skin and granulomatous MF51. Treatment Radiotherapy may be effective, but experience is still limited. Rapid recurrences after surgical excision have been reported.Sezary SyndromeSÉZARY SYNDROME Definition Sézary syndrome (SS) is defined historically by the triad of erythroderma, generalized lymphadenopathy, and the presence of neoplastic T cells (Sézary cells) in the skin, lymph nodes, and peripheral blood (see Table 120.4). However, distinguishing SS from benign forms of erythroderma can be extremely difficult. Criteria for the diagnosis of SS include demonstration of a T-cell clone in the peripheral blood (preferably the same T-cell clone as in the skin), in combination with an absolute Sézary cell count ≥1000 cells/mcl or immunophenotypical abnormalities (an expanded CD4+ T-cell population resulting in a CD4/ CD8 ratio >10 and/or aberrant expression of pan-T-cell antigens)3,52. While SS is often designated as a leukemic phase or variant of MF, more recent studies have revealed major genomic and phenotypical differences between these two entities, suggesting that SS and MF should be considered as separate lymphomas arising from distinct functional T-cell subsets16,53. Epidemiology SS is a rare disease accounting for less than 5% of all CTCL (see Table 120.1). It occurs exclusively in adults. Clinical features SS is characterized by erythroderma, which may be associated with marked exfoliation, edema and lichenification; it is intensely pruritic (Fig. 120.9A). Lymphadenopathy, alopecia, onychodystrophy, and palmoplantar hyperkeratosis are common findings. The overt clinical picture may be preceded by a non-diagnostic dermatitis. The prognosis is generally poor, with an overall 5-year survival of ~25%. Most patients die of opportunistic infections due to immunosuppression. Pathology The histologic features in SS may be similar to those in MF. However, the cellular infiltrates in SS are more often monotonous, and epidermotropism may sometimes be absent. In up to one-third of skin biopsies from patients with otherwise classic SS, the histologic findings may be nonspecific54. Involved lymph nodes characteristically show a dense, monotonous infiltrate of Sézary cells with effacement of the normal lymph node architecture. The bone marrow may be involved, but the infiltrates are often sparse and mainly interstitial. The neoplastic T cells have a CD3+, CD4+, CD8− phenotype, characteristically lack CD7 and CD26 expression, and express programmed death-1 (PD-1; CD279) in almost all cases (Fig. 120.9B)55.More Sezary SyndromePathogenesis The pathogenesis of SS is unknown. Conclusive evidence of an etiologic role for HTLV-1 is lacking. In SS, the neoplastic CD4+ T cells have the phenotype of a central memory T-cell subset and thus are capable of circulating between skin, lymph nodes and peripheral blood, while the neoplastic cells in MF are derived from non-circulating skin resident effector memory T cells53,. In addition to these phenotypical differences, SS and MF have major genomic differences16, in particular gross chromosomal instability with highly recurrent gains and losses in SS. These include deletions involving chromosomes 10q22-25 (harbors PTEN) and 17p12-13 (includes TP53) and gains involving chromosomes 8q22-24 (includes MYC), 10p11.2, and 17q22-2518,56,57. Gene expression studies showed increased expression of PLS3 (T-plastin), TWIST1, and CD158k/KIR3DL2, which might be used as diagnostic markers58. Differential diagnosis Differentiation between SS and non-neoplastic forms of erythroderma may be extremely difficult59. The differential diagnosis includes erythroderma secondary to psoriasis, atopic dermatitis or other forms of dermatitis, pityriasis rubra pilaris, and drug reactions as well as idiopathic erythroderma (see Ch. 10). Demonstration of an identical T-cell clone in skin and peripheral blood is an important diagnostic criterion favoring SS. Demonstration of a predominant CD3+, CD4−, CD8+ T-cell population in the skin and peripheral blood is highly suggestive of actinic reticuloid (see Ch. 87)60. Treatment Being a systemic disease (leukemia) by definition, systemic treatment is required. Skin-directed therapies like PUVA or potent topical corticosteroids may be used as adjuvant therapy. Extracorporeal photopheresis (ECP), either alone or in combination with other treatment modalities, has been suggested as the treatment of choice in SS and erythrodermic MF, with overall response rates of 30-80%, and complete response rates of 14-25%61. This great variation in response rates may reflect differences in patient selection and/or concurrent therapies. The suggested superiority of ECP over traditional low-dose chemotherapy regimens has not yet been substantiated by randomized controlled trials62. Beneficial effects have also been reported with IFN-α (either alone or in combination with PUVA therapy) as well as prolonged treatment with methotrexate or low-dose chlorambucil plus prednisone, but complete responses are uncommon. CHOP or CHOP-like regimens may produce higher response rates, but these responses are generally short-lived. Recent studies have observed possible benefits with bexarotene, denileukin diftitox, HDACi and (low-dose) alemtuzumab (anti-CD52), but the long-term effects of these therapies remain to be established35,36,61. Allogeneic hematopoietic stem cell transplantation may have curative potential, even in patients with advanced disease (see MF treatment).Adult T cell leukemia/lymphomaADULT T-CELL LEUKEMIA/LYMPHOMA Definition Adult T-cell leukemia/lymphoma (ATLL) is a type of T-cell neoplasm etiologically associated with HTLV-1. Skin lesions are generally a manifestation of widely disseminated disease. However, a slowly progressive form that sometimes has only cutaneous lesions has been described (smoldering variant)63. Epidemiology ATLL is endemic in areas with a high prevalence of HTLV-1 in the population, such as southwestern Japan, the Caribbean Islands, and parts of Central Africa. In addition, a high prevalence is seen in Jewish individuals whose ancestors were from Mashad, Iran. However, only a minority of seropositive patients eventually develop ATLL. The disease occurs in adults, and men are affected more frequently than women. Vertical transmission is more common than horizontal transmission. Clinical features Most patients present with acute ATLL characterized by the presence of leukemia, lymphadenopathy, organomegaly, hypercalcemia, and frequently skin lesions; it has a poor prognosis. Chronic and smoldering variants often present with patches, plaques and papular skin lesions, which may closely resemble MF, and circulating neoplastic T cells are few or absent. Such cases have a more protracted clinical course, but progression to a high-grade malignant disseminated form of the disease may occur. Pathology Skin lesions demonstrate a superficial or more diffuse infiltration of small, medium-sized or large pleomorphic T cells, which often display marked epidermotropism. The histologic picture may be indistinguishable from MF. Skin lesions in the smoldering type may have sparse dermal infiltrates with only slightly atypical cells. The neoplastic T cells express a CD3+, CD4+, CD8−, CD25+ phenotype, and - as in SS - strongly express PD-164. Differential diagnosis Differentiation between chronic or smoldering variants of ATLL and MF may be extremely difficult, particularly in endemic areas. In such cases, a definite diagnosis of ATLL requires demonstration of clonally integrated HTLV-1. Treatment ATLL may be treated with a combination of zidovudine and IFN-α, but in most cases, systemic chemotherapy is required65. In Japan, mogamulizumab (anti-CCR4) is approved for treating ATLL. For chronic and smoldering disease mainly affecting the skin, skin-directed therapies as in MF are preferred.Primary cutaneous CD30-positive lymphoproliverative disordersPRIMARY CUTANEOUS CD30-POSITIVE LYMPHOPROLIFERATIVE DISORDERS Primary cutaneous CD30-positive lymphoproliferative disorders represent the second most common group of CTCL, accounting for ~25% of CTCL (see Table 120.1). This group includes primary cutaneous anaplastic large cell lymphoma (C-ALCL), lymphomatoid papulosis (LyP), and borderline cases. C-ALCL and LyP have overlapping clinical, histologic, and immunophenotypical features and form a spectrum of disease. Thus, histologic criteria alone are often insufficient to distinguish between the two ends of the spectrum. In the end, the clinical appearance and course are used as decisive criteria for the definite diagnosis and choice of treatment. The term "borderline case" refers to patients in whom, despite careful clinicopathologic correlation, a definite distinction between C-ALCL and LyP cannot be made. Longitudinal clinical evaluation will generally disclose whether the patient has C-ALCL or LyP59. Cases previously designated as regressing atypical histiocytosis, as well as rare cases of primary cutaneous Hodgkin lymphoma with an indolent clinical course, also belong to this spectrum66. Primary cutaneous CD30-positive lymphoproliferative disorders should be differentiated from: (1) skin involvement by systemic ALCL; (2) CD30-positive transformed MF; (3) other well-defined types of CTCL, which may sometimes express the CD30 antigen; and (4) reactive skin conditions with infiltrates containing CD30-positive blast cells, including various viral infections, arthropod bite reactions, scabies, and atopic dermatitis67 (see Table 120.2). Guidelines for the diagnosis and treatment of primary cutaneous CD30-positive lymphoproliferations are provided in Fig. 120.10.Primary Cutaenous Anaplastic Large Cell LymphomaPrimary Cutaneous Anaplastic Large Cell Lymphoma Definition Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is composed of large cells with an anaplastic, pleomorphic or immunoblastic cytomorphology and expression of the CD30 antigen by the majority (>75%) of tumor cells. Patients should not have clinical evidence of or a history of MF. In such individuals, a diagnosis of tumor stage MF with blastic transformation is more likely. Epidemiology These lymphomas account for ~12% of all CTCLs (see Table 120.1). They predominantly affect adults and are rare in children or adolescents. The male-to-female ratio is approximately 2 : 1. Clinical features Most patients present with solitary or localized nodules or tumors (sometimes papules) that often develop ulceration (Fig. 120.11A). Multifocal lesions are seen in about 20% of patients. The skin lesions may show partial or complete spontaneous regression, as in LyP. These lymphomas frequently relapse in the skin. Extracutaneous dissemination occurs in ~10% of patients, and it mainly involves the regional lymph nodes. The prognosis is usually favorable, with a 10-year disease-related survival exceeding 85%66,68. Pathology Histologically, these lymphomas show diffuse non-epidermotropic infiltrates with cohesive sheets of large CD30-positive tumor cells (Fig. 120.11B). In most cases, the tumor cells have the characteristic morphology of anaplastic cells, with round, oval or irregularly shaped nuclei, prominent (eosinophilic) nucleoli, and abundant cytoplasm. Less commonly (20-25%), tumor cells have a pleomorphic, immunoblastic, or Reed-Sternberg cell-like appearance. The mitotic index is generally high. Reactive lymphocytes are often present at the periphery of the tumor. Ulcerating lesions may show an LyP-like histology with an abundant inflammatory infiltrate of reactive T cells, histiocytes, eosinophils, neutrophils, and relatively few CD30-positive cells. In such cases, epidermal hyperplasia may be prominent. Intralymphatic complexes of tumor cells are common69, and purely intralymphatic cases of C-ALCL have been observed70. Immunophenotype The neoplastic cells often express a CD4+ T-cell phenotype with variable loss of CD2, CD5 and/or CD3. Some cases (<5%) have a CD8+ T-cell phenotype. CD30 must be expressed by the majority of neoplastic cells. Expression of cytotoxic proteins (granzyme B, TIA-1, perforin) is noted in ~70% of cases, while MUM1/IRF4 (multiple myeloma oncogene 1/interferon regulatory factor 4) is expressed in almost all cases71. Unlike systemic ALCL, most C-ALCLs express CLA (cutaneous lymphocyte antigen), but do not express EMA (epithelial membrane antigen) or ALK (anaplastic lymphoma kinase); the latter is indicative of a t(2;5) chromosomal translocation. Coexpression of CD56 is observed in rare cases, but does not appear to be associated with an unfavorable prognosis72.More Primary Cutaneous Anaplastic Large Cell LymphomaGenetic features The t(2;5) translocation, which is found predominantly in systemic ALCL in children, is not present in the vast majority of C-ALCL. However, unusual cases of ALK+ C-ALCL have been reported, including cases with: (1) strong nuclear and cytoplasmic staining characteristic of the t(2;5) chromosomal translocation; or (2) expression of cytoplasmic ALK protein, indicative of a variant translocation73,74. Rearrangements of the DUSP22-IRF4 locus on chromosome 6p25.3 are found almost exclusively in C-ALCL (~25%) and in a small subset of LyP75,76. Frequent chromosomal aberrations, affecting almost half of the patients, are gains of 7q31 and losses on 6q16-21 and13q3418,77. In contrast to tumor stage MF and PTCL, NOS, loss of 9p21.3 is rarely observed in C-ALCL. High expression of skin-homing chemokine receptor genes CCR10 and CCR8 is seen in C-ALCL, which may explain its affinity for the skin and low incidence of dissemination to extracutaneous sites77. Treatment Radiotherapy or surgical excision is an initial treatment in patients presenting with a solitary or a few localized nodules or tumors. However, if a solitary lesion disappears spontaneously, no further therapy is required. Patients presenting with multifocal skin lesions can best be treated with radiotherapy (if there are only a few lesions), low-dose methotrexate, retinoids, or interferon-α78. Patients who present with or develop extracutaneous disease or those rare patients with rapidly progressive skin disease should be treated with doxorubicin-based multi-agent chemotherapy. Early aggressive therapy may also be considered in patients presenting with extensive skin lesions on one or both legs, since such patients are at risk for a more aggressive clinical course68,79. Brentuximab vedotin (anti-CD30 monoclonal antibody coupled to the anti-tubulin agent monomethyl auristatin E) is FDA-approved for relapsed systemic ALCL and has been used for C-ALCL and MF expressing CD30, but experience is still too limited to determine which patients will benefit most from this treatment80. cytoplasm.Lymphomatoid PapulosisLymphomatoid Papulosis Definition Lymphomatoid papulosis (LyP) is defined as a chronic, recurrent, self-healing papulonecrotic or papulonodular skin disease with histologic features suggestive of a (CD30-positive) malignant lymphoma. Since the introduction of the term LyP in 1968 by Macaulay81, there has been continued discussion as to whether LyP is a malignant, premalignant, or benign condition. Because of the overlapping clinical and histologic features between LyP and C-ALCL, including the presence of an aberrant T-cell phenotype, the presence of clonally rearranged TCR genes in 60-70% of the patients, and the presence of identical T-cell clones in LyP lesions and associated lymphoma lesions, LyP is best regarded as a low-grade variant of CTCL. Pathogenesis The initiating event in LyP is unknown. Several authors have suggested a viral etiology. However, studies searching for an etiologic role for HTLV-1, EBV, and other herpes viruses, including herpes simplex virus types 1 and type 2 and human herpesvirus-6, have been consistently negative. The mechanisms involved in the spontaneous disappearance of skin lesions, or in the tumor progression observed in some patients with LyP, have not yet been identified. It has been suggested that interactions between CD30 and its ligand (CD30L) may contribute to apoptosis of the neoplastic T cells and the subsequent regression of the skin lesions, but the exact mechanism is as yet unknown82. Unresponsiveness to the growth inhibitory effect of transforming growth factor-β (TGF-β) due to a mutation in the gene that encodes the TGF-β type I receptor on the CD30-positive tumor cells has been suggested as one of the possible mechanisms in tumor progression83. Epidemiology LyP accounts for approximately 15% of all CTCL (see Table 120.1). It may occur at any age. The youngest patient reported to date was 8 months old, and the oldest was 84 years of age. In large series, the average age of onset varies between 35 and 45 years. The male-to-female ratio is approximately 1.5 : 1.Lymphomatoid PapulosisClinical features The typical skin lesions in LyP are red-brown papules and nodules that may develop central hemorrhage, necrosis and crusting; they subsequently disappear spontaneously within 3 to 12 weeks. Characteristically, skin lesions in different stages of evolution coexist (Fig. 120.12A). The papulonodules may leave transient hypopigmented or hyperpigmented macules and, occasionally, superficial atrophic (varioliform) scars, or they may disappear without ulceration or sequelae. The number of lesions varies from several to more than one hundred. Lesions may be localized, sometimes clustered within rather well-defined areas, or generalized. The predominant sites of involvement are the trunk and limbs. The eruption is generally asymptomatic. The duration of the disease ranges from several months to more than 40 years. In up to 20% of patients, LyP may be preceded by, associated with, or followed by another type of cutaneous or systemic lymphoma, generally MF, C-ALCL or Hodgkin lymphoma66,84. However, the prognosis is usually excellent. In a study of 118 patients with LyP, only five patients (4%) developed a systemic lymphoma, and only two patients (2%) died of systemic disease over a median follow-up period of 77 months66. Risk factors for the development of a systemic lymphoma are unknown. Pathology The histologic picture of LyP is extremely variable, but in part it correlates with the age of the sampled skin lesion (Fig. 120.12B). In addition, several histologic types of LyP have been described (Table 120.6; Fig. 120.12C), with LyP type A being the classic and most common type of LyP (>75%)66,85. It should be noted that different types of LyP may occur in different but concurrent lesions, and that a single LyP lesion may show histologic features of different subtypes of LyP. Knowledge of the variable histologic presentations of LyP is more important for pathologists than for clinicians as the subtype has no therapeutic or prognostic implications. Differential diagnosis LyP is often diagnosed clinically as more common entities. Small recurrent LyP lesions on the trunk are frequently misinterpreted as folliculitis or arthropod bites for years, and notably, CD30+ cells can be observed in many benign conditions67. On the other hand, because of the presence of multifocal skin lesions with the histologic features of CD30-positive CTCL, LyP patients are regularly treated unnecessarily with multi-agent chemotherapy by physicians not familiar with this condition. Obviously, when the clinical features are taken into account, differentiation between LyP and the malignant lymphomas it may resemble histologically is not difficult. Because of the clinical similarities between LyP and pityriasis lichenoides, a relationship between the two conditions was initially suggested. More recently, clonal T-cell populations have been demonstrated in skin biopsies of both conditions. However, differentiation is generally not difficult. Pityriasis lichenoides occurs more often in younger patients, is often relatively short-lived, does not develop nodular lesions, and rarely, if ever, progresses to a lymphoma. Histologically, the diseases are usually easily distinguished, and CD30-positive blast cells are generally not seen in pityriasis lichenoides. Treatment The treatment of patients with LyP is unsatisfactory78. Topical or systemic corticosteroids and antibiotics are not effective. Aggressive treatment modalities such as systemic chemotherapy or TSEB irradiation may produce complete remissions, but after discontinuation of therapy, the LyP lesions generally reappear within weeks or months, and the disease follows its natural course. Since a curative therapy is not available and none of the available treatment modalities affects the natural course of the disease, the short-term benefits of active treatment should be balanced carefully against potential side effects66,78. In patients with relatively few non-scarring lesions, active treatment is not necessary. In the case of cosmetically disturbing lesions (e.g. scarring or many papulonodules), low-dose oral methotrexate (5-20 mg/week) is the most effective therapy for reducing the number of skin lesions. Beneficial effects have been reported from PUVA, topical mechlorethamine or carmustine, and low-dose etoposide. When larger skin tumors develop in the course of LyP, they can be observed for a period of 4 to 12 weeks for the possibility of spontaneous remission. If spontaneous resolution does not occur, such lesions can be excised or treated with radiotherapy. Because of the potential risk for developing a systemic lymphoma, long-term follow-up is required in all patients with LyP.Subcutaneous panniculitis like T cell lymphomaSUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA Definition In the WHO-EORTC classification (2005) and the most recent WHO classification (2008/2016), subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is defined as a cytotoxic T-cell lymphoma characterized by the presence of primarily subcutaneous infiltrates of small, medium-sized or large pleomorphic T cells with an α/β+ T-cell phenotype, in association with many macrophages3,4. In past classification schemes, the SPTCL category included cases with an α/β T-cell phenotype (75%) and cases with a γ/δ T-cell phenotype (25%)1,2. However, several studies have shown clinical, histologic and immunophenotypical differences between cases of SPTCL with an α/β T-cell phenotype and those with a γ/δ T-cell phenotype, suggesting that they represent different entities. Whereas SPTCLs with an α/β T-cell phenotype are homogeneous with a rather indolent clinical behavior in many patients, SPTCL with a γ/δ T-cell phenotype overlaps with other types of γ/δ- positive T-cell lymphoma and runs a very aggressive clinical course86,87. Therefore, in both the WHO-EORTC classification and the most recent WHO classification, the term SPTCL is only used for cases with an α/β+ T-cell phenotype, whereas cases with a γ/δ+ T-cell phenotype are included in the category of primary cutaneous gamma/delta T-cell lymphoma (Table 120.7). Epidemiology SPTCL is a rare condition, accounting for <1% of all CTCL. It may occur in adults as well as in young children, and both sexes are equally affected. Clinical features Patients generally present with a solitary or multiple nodules or deeply seated plaques with a diameter varying from 1 to 20 cm. The skin lesions involve primarily the extremities and the trunk and less commonly the face; when the nodules and plaques resolve, they may be replaced by areas of lipoatrophy (Fig. 120.13A). Ulceration is uncommon. Systemic symptoms such as fever, fatigue, and weight loss may be present in over half of the patients. Laboratory abnormalities including cytopenias and elevated liver function tests are common, but a frank hemophagocytic syndrome is observed in only ~15% of patients87. Dissemination to extracutaneous sites is rare and while hepatosplenomegaly may be seen, it is generally not due to lymphomatous involvement. SPTCL may be preceded for years or decades by a seemingly benign panniculitis. Up to 20% of patients have an associated autoimmune disease, most commonly systemic lupus erythematosus. Recent studies have suggested overlapping features between SPTCL and lupus profundus88. SPTCL has a favorable prognosis with a 5-year overall survival of ~80%87. However, the presence of hemophagocytic syndrome is associated with a more unfavorable prognosis.Panniculitis like T cell lymphomaPathology Subcutaneous infiltrates simulating a lobular panniculitis are seen in SPTCL. Small, medium-sized, or sometimes large pleomorphic T cells with hyperchromatic nuclei are present and are often admixed with many macrophages. The overlying epidermis and dermis are typically uninvolved. Rimming of individual fat cells by neoplastic T cells is a helpful, although not entirely specific, diagnostic feature (Fig. 120.13B). Necrosis, karyorrhexis, and cytophagocytosis are common findings. In the early stages, the neoplastic infiltrates may lack significant atypia and a heavy inflammatory infiltrate may predominate. Immunophenotype These lymphomas have a TCRα/β+, CD3+, CD4−, CD8+ T-cell phenotype, with expression of cytotoxic proteins. The neoplastic T cells express βF1 and are negative for CD56, facilitating differentiation from primary cutaneous gamma/delta T-cell lymphoma with subcutaneous involvement and panniculitis-like lesions (see Table 120.7). CD30 is rarely, if ever, expressed. Treatment While doxorubicin-based chemotherapy has traditionally been used, recent studies suggest that more conservative immunosuppressive regimens (e.g. prednisone, cyclosporine) may be effective and should initially be considered in patients with SPTCL without an associated hemophagocytic syndrome. In patients presenting with a solitary lesion, local radiotherapy may be effectiveExtranodal NK/T-Cell lymphoma nasal typeEXTRANODAL NK/T-CELL LYMPHOMA, NASAL TYPE Definition Extranodal NK/T-cell lymphoma, nasal type is nearly always an EBV-positive lymphoma with an NK-cell, or more rarely a cytotoxic T-cell, phenotype. The skin is the most common site of involvement after the nasal cavity/nasopharynx, and skin involvement may be a primary or secondary manifestation of the disease. Epidemiology Extranodal NK/T-cell lymphoma is a rare disease, particularly in Europe and the US. It is more common in Asia, Central America, and South America. Patients are primarily adults, with a predominance of men. Clinical features Patients generally present with multiple plaques or tumors on the trunk and extremities or, in the case of nasal NK/T-cell lymphoma, with a midfacial destructive tumor (previously referred to as lethal midline granuloma)89,90. Ulceration is common (Fig. 120.14). Although patients presenting with only skin lesions have a somewhat better prognosis than patients presenting with both cutaneous and extracutaneous disease, the disease in both groups has a very aggressive clinical behavior and requires the same type of treatment. Pathology These lymphomas are characterized by dense infiltrates involving the dermis and often the subcutis. Prominent angiocentricity and angiodestruction are often accompanied by extensive necrosis. NK/T-cell lymphoma has a broad cytologic spectrum ranging from small to large cells, with most cases consisting of medium-sized cells with irregular or oval nuclei, moderately dense chromatin, and pale cytoplasm. In some cases, a heavy inflammatory infiltrate of small lymphocytes, histiocytes, plasma cells, and eosinophils can be seen. The T-cell receptor usually has a germline configuration, but can be clonally rearranged in the rare tumors with a cytotoxic T-cell phenotype. Immunophenotype The neoplastic cells express CD2, CD56, cytoplasmic CD3ε, and cytotoxic proteins (TIA-1, granzyme B, perforin), but they lack surface CD3. Detection of EBV by in situ hybridization and expression of cytotoxic proteins is required for diagnosis. Treatment In patients with localized disease, radiotherapy is the preferred treatment91. When more advanced, these lymphomas have an aggressive clinical behavior and are often resistant to chemotherapy. Recently, an intensive chemotherapy regimen including L-asparaginase (the SMILE regimen) showed promising results92Primary cutaneous CD8 positive aggressive epidermotropic cytotoxic T cell lymphomaPRIMARY CUTANEOUS CD8-POSITIVE AGGRESSIVE EPIDERMOTROPIC CYTOTOXIC T-CELL LYMPHOMA These tumors are characterized by a proliferation of epidermotropic CD8-positive cytotoxic T cells and an aggressive clinical behavior93,94. Differentiation from other types of CTCL expressing a CD8-positive cytotoxic T-cell phenotype - >50% of patients with pagetoid reticulosis and rare cases of MF, LyP, and C-ALCL - is based on the clinical presentation and clinical behavior. In the latter conditions, no differences in clinical presentation or prognosis are observed between CD4+ and CD8+ cases. Clinically, these lymphomas are characterized by the presence of localized or disseminated eruptive papules, nodules and tumors with central ulceration and necrosis or by superficial, hyperkeratotic patches and plaques (Fig. 120.15). They may disseminate to other visceral sites (lung, testis, central nervous system, oral mucosa), but lymph nodes are often spared93. Histologically, these lymphomas show strongly epidermotropic, band-like to diffuse infiltrates of small, medium-sized or large pleomorphic T cells with a CD3+, CD4−, CD8+, CD7−/+, CD45RA+, granzyme B+, perforin+, TIA-1+ phenotype93. The epidermis may be acanthotic or atrophic, and there may be necrotic keratinocytes, ulceration and variable spongiosis, sometimes with blister formation. Invasion and destruction of cutaneous adnexal structures are commonly seen. Angiocentricity and angioinvasion may be present. These lymphomas run an aggressive clinical course and should be treated with systemic chemotherapy.PRIMARY CUTANEOUS GAMMA/DELTA T-CELL LYMPHOMA Primary cutaneous gamma/delta T-cell lymphoma (PCGD-TCL) is a lymphoma composed of a clonal proliferation of mature, activated gamma/delta T cells with a cytotoxic phenotype. This group includes cases previously known as SPTCL with a gamma/delta T-cell phenotype. PCGD-TCL should be differentiated from SPTCL, other types of aggressive cytotoxic cutaneous T/NK-cell lymphomas, and tumor stage MF, but this may prove extremely difficult and requires integration of clinical, histologic, phenotypical, and molecular genetic data (see Tables 120.2 and 120.7). It should be noted that TCRγ expression is not only found in PCGD-TCL, but has also been reported in other types of CTCL, including rare cases of otherwise classic MF32,33. PCGD-TCL generally presents with disseminated plaques and/or ulceronecrotic nodules or tumors, particularly on the extremities, but other sites may be affected87,95. Involvement of mucosal and other extranodal sites is frequently observed, but involvement of lymph nodes, spleen or bone marrow is uncommon. In patients with panniculitis-like tumors, a hemophagocytic syndrome may occur. Histologically, three major patterns of involvement can be seen: epidermotropic, dermal, and subcutaneous. Often more than one histologic pattern is present within a single biopsy specimen or in different biopsy specimens from the same patient. The epidermal pattern can vary from mild epidermotropism to a marked pagetoid reticulosis-like infiltrate. Rimming of fat cells may be observed when there is subcutaneous involvement, similar to SPTCL. Angiocentricity and angiodestruction are commonly seen. The neoplastic cells are generally medium to large in size with coarsely clumped chromatin, and they have a TCRγ+, TCRα/β (βF1)−, CD3+, CD2+, CD4−, CD5−, CD7+/−, CD8−, CD56+ phenotype with strong expression of cytotoxic proteins. Co-expression of both TCRγ and TCRα/β may be observed. Most patients have aggressive, often rapidly fatal disease, which is resistant to multi-agent chemotherapy. Patients with subcutaneous fat involvement may have a worse prognosis in comparison to patients with epidermal or dermal disease only95Primary cutaneous CD4 postitive small/medium T-Cell lymphoproliferative disorderPRIMARY CUTANEOUS CD4-POSITIVE SMALL/MEDIUM T-CELL LYMPHOPROLIFERATIVE DISORDER In recent classifications, this type of CTCL is listed as a provisional entity characterized by a predominance of small to medium-sized CD4- positive pleomorphic T cells without (a history of) patches and plaques typical of MF and, in most cases, a favorable clinical course3,4. However, there has been much debate on the definition, classification and correct terminology of this condition. Characteristically, this lymphoproliferative disorder presents with a solitary plaque or tumor, generally on the face, the neck or the upper trunk96. Histologically, lesions show dense, diffuse or nodular infiltrates within the dermis with a tendency to infiltrate the subcutis. Epidermotropism may be present focally. There is a predominance of small/medium-sized CD3+, CD4+, CD8−, CD30− pleomorphic T cells. A small proportion (<30%) of large pleomorphic cells may be present. These medium-sized to large atypical T cells typically express programmed death-1 (PD-1), Bcl-6 and CXCL13, suggesting a common follicular T-helper-cell phenotype97,98. The proliferative rate is generally low. In most cases, a considerable admixture with reactive CD8- positive T cells, CD20+ B cells, plasma cells and histiocytes, including multinucleated giant cells, is observed. These lesions can be treated with excision, intralesional corticosteroids or local radiotherapy, and their prognosis is excellent. The clinical and histologic characteristics of the patients presenting with a solitary lesion are identical to those of nodular pseudo-T-cell lymphomas, including the presence of clonal T cells98. There is increasing doubt whether such cases should be considered genuine malignant lymphomas. Thus, the 2016 update of the WHO classification chose the term primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disorder. Primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disorders presenting with any of the following are rare and may have a more aggressive clinical course: (1) generalized skin lesions; (2) rapidly growing bulky tumors; (3) a high proliferative fraction; or (4) a very low percentage of admixed CD8+ T cells99. Such cases should be fully staged and are perhaps better considered as primary cutaneous PTCL, NOS (see below). Recent reports have described skin lesions with a monotonous population of small to medium-sized pleomorphic CD8+ T cells, also with a low proliferative fraction, but - in contrast to the CD4+ cases - very few admixed inflammatory cells100,101. These primary cutaneous acral CD8-positive T-cell lymphomas, which present with solitary lesions, predominantly on the ear or the face or other acral sites, also have an excellent prognosis.Primary cutaneous peripheral T cell lymphomaPRIMARY CUTANEOUS PERIPHERAL T-CELL LYMPHOMA, NOS The designation "primary cutaneous peripheral T-cell lymphoma (PTCL), NOS (not otherwise specified)" is maintained for CTCLs that do not fit into any of the better-defined subtypes outlined in Table 120.1. It is therefore a diagnosis of exclusion. Clinically, these patients present with solitary or localized, but more frequently generalized, nodules or tumors102 (Fig. 120.16). Histologically, there are nodular or diffuse infiltrates with variable numbers of medium-sized to large pleomorphic or immunoblast-like T cells. Epidermotropism is generally mild or absent. Most cases have an aberrant CD4+ T-cell phenotype with variable loss of pan-T-cell antigens. CD30 staining is negative or restricted to a few scattered tumor cells. Rare cases may show coexpression of CD56. Patients should be treated with systemic chemotherapy, but the prognosis is generally poor, with a 5-year survival of less than 20%