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is seen more frequently in adult patients, but children can also be affected.4
Customarily, on the basis of its extremely variable histopathology, LyP has been divided into five types with similar prognosis, although distinguishing them is impor- tant for the differential diagnosis from more aggressive types of lymphoma.5 Although more descriptive terms have been proposed, in 2017 the World Health Organization (WHO) categorized LyP using consecutive alphabetical letters.6 Type A is the most frequent form of LyP, accounting for 80% of cases. Tumor cells are typically CD4+ and CD30+ and appear scattered or in small clusters, accompanied by numerous inflammatory cells, including neutrophils, eosinophils and small lymphocytes. The main differential diagnoses include reactive lesions, such as insect bites, and pityriasis lichenoides et varioliformis acuta (PLEVA).7 Type B is uncommon, accounting for 5% of cases, and has the same CD4+, CD8– immunopheno- type.7 It has a histology similar to that of plaque-stage MF with an epidermotropic infiltrate of small, atypical CD30+ cells, which is its main differential diagnosis; less frequent- ly it must be distinguished from cutaneous epidermotrop- ic gamma/delta lymphoma.5 Type C makes up around 10% of LyP cases and has a histology very similar to that of pcALCL, with a nodular cohesive infiltrate of large CD30+, CD4+, CD8– pleomorphic and anaplastic tumor cells featuring mitotic figures and abundant cytoplasm.7 Apart from pcALCL, other entities, such as transformed MF, peripheral T-cell lymphoma not otherwise specified, and adult T-cell lymphoma/leukemia, may have a similar histology.5 Types D and E have only been described rela- tively recently, and are usually characterized by a cytotox- ic phenotype, with CD8+ and CD30+ lymphocytes. Biopsies from patients with type D LyP show prominent epidermotropism of atypical small-to-medium-sized pleo- morphic cells. There may be deep dermal and perivascular infiltrates. This variant accounts for about 5% of cases and needs to be differentiated from pagetoid reticulosis, a peculiar CD8+ form of MF, from more aggressive lym- phomas such as primary cutaneous aggressive epider- motropic CD8+ cytotoxic T-cell lymphoma, and from cutaneous gamma/delta lymphoma.8 Accounting for fewer than 5% of cases, type E LyP shows more extensive necrosis and ulceration due to angiocentric and angiode- structive infiltrates of mostly medium-sized, pleomorphic CD8+ and CD30+ lymphocytes with hemorrhage, vascular occlusion and thrombi, admixed with some eosinophils.9 Although clinically indolent, the histology can be con- fused with that of extranodal NK/T-cell lymphoma, nasal type, cutaneous gamma/delta lymphoma or ALCL (prima- ry cutaneous or systemic form) with angiocentric and angiodestructive growth. It is important to highlight that histological differential diagnoses of LyP (such as aggres- sive epidermotropic CD8+ cytotoxic T-cell lymphoma or MF) must be excluded by clinicopathological correlation based on characteristic clinical grounds with the typical "waxing and waning" presentation of LyP.
Recently, the detection of rearrangements of the DUSP22-IRF4 locus on chromosome 6p25.3 has enabled the identification of a new molecular-based type of LyP with a characteristic histological pattern.10
Lymphomatoid papulosis with 6p25.3 rearrangements
This molecular alteration at the DUSP22-IRF4 locus is less frequent in LyP than in pcALCL and accounts for
fewer than 5% of cases of LyP. Typically, patients are older than those with other forms of LyP, and their lesions are characterized by a biphasic histological pattern showing, on the one hand, extensive epidermotropism with CD30+ small-to-medium-sized T-lymphocytes that simulate pagetoid reticulosis lesions and, on the other, a dermal neoplastic infiltrate composed of large T cells with strong CD30positivity.11
T-cell receptor clonality
haematologica | 2019; 104(2)
CD30+ primary cutaneous LPD
Detection of T-cell receptor clonality differs significantly between LyP types.12 This difference might be related to the number of tumor cells present in the infiltrate, which is lower in type A than in type C, hindering the detection technique in paraffin-embedded tissues. LyP presents atypical evolution for a peripheral T-cell lymphoma, exhibiting self-healing lesions and multiple outbreaks. T- cell receptor clonality studies have been performed in var- ious LyP lesions to investigate the potential role of foreign antigens and the relationship between LyP and other cuta- neous T-cell lymphomas in cases with overlapping histo- logical findings. Chott et al. showed that multiple skin lesions and associated T-cell lymphomas (MF and ALCL) were clonally related in most LyP patients, which suggests that a non-random genetic event initiates the disease.13 Shared clonality has been confirmed for LyP and MF lesions occurring in the same patients by de la Garza Bravos et al.14
T-cell receptor-γ expression is considered a feature of primary cutaneous gamma-delta T-cell lymphoma, and is rare in other types of primary cutaneous lymphoma. However, there are cases of type D LyP with a cytotoxic phenotype and T-cell receptor-γ expression that, unlike in primary cutaneous gamma-delta T-cell lymphoma, is not associated with worse prognosis.15
Other findings in lymphomatoid papulosis
SATB1 (special AT-rich sequence-binding protein 1) is an important thymocyte nuclear protein, a chromatin organ- izer that is crucial to the development of T-lympho- cytes.16,17 SATB1 plays a role in inducing resistance to the death of Sézary cells and has been implicated in the patho- genesis of the leukemic form of cutaneous T-cell lym- phoma-Sézary syndrome.18 Sun et al. investigated its expression in a large cohort of patients with CD30+ lym- phoproliferative disorders, and studied the potential for its use in classifying CD30+ lymphoproliferative disorders with differential clinicopathological behaviors and prog- noses.19 They identified SATB1 expression in anaplastic T cells in 91.7% of LyP cases and in 38.1% of pcALCL cases. SATB1 cases showed T-helper 17 polarization with expression of T-helper 17 cytokines and repressed T- helper 1-related genes.19 They also described a better response to methotrexate and interferon treatment in cases with high levels of SATB1 expression. Furthermore, these cases showed more prominent epidermal hyperpla- sia and granulocytic infiltration.19 Sun et al. postulated that the variability of SATB1 expression in CD30+ lymphopro- liferative disorders could be related to the extent of DNA methylation.19
Tumor necrosis factor receptor (TNFR)-associated factor 1 (TRAF1) is involved in intracellular signal transduction of a range of TNFR, including CD30 and those associated with nuclear factor-kB activation.20 Assaf et al. studied the expression of TRAF1 using one antibody that recognized
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