Pagetoid Reticulosis: Presentation, Diagnosis, and Subtypes

Pagetoid reticulosis is a rare form of cutaneous T-cell lymphoma characterized by localized skin lesions that can mimic other dermatological conditions. Its resemblance to more common disorders often leads to delayed diagnosis, making awareness crucial for early detection and management.

Recognizing its key clinical and pathological features is essential for differentiation from other lymphoproliferative diseases.

Dermatological Presentation

Pagetoid reticulosis presents as a solitary, slow-growing skin lesion, most commonly on the lower legs. The lesion appears as a well-demarcated, scaly, erythematous plaque with a slightly elevated border, often resembling psoriasis or eczema. Unlike other cutaneous lymphomas, it remains localized without systemic spread, distinguishing it from more aggressive variants of mycosis fungoides.

Over time, the plaque may develop hyperkeratosis, giving it a rough, verrucous texture, sometimes mistaken for hypertrophic lichen planus or superficial basal cell carcinoma. Fine scaling and mild atrophy can be observed, particularly in long-standing cases. Pruritus is generally absent or mild, unlike the intense itching seen in inflammatory dermatoses. The absence of ulceration or significant pain further differentiates it from aggressive cutaneous malignancies.

Dermoscopy reveals a homogeneous erythematous background with fine white scales and dotted or glomerular vessels. While not exclusive to Pagetoid reticulosis, these vascular patterns help narrow the differential diagnosis when combined with clinical history and lesion morphology. The slow progression, often persisting for years without significant change, reinforces its classification as a localized variant of cutaneous T-cell lymphoma.

Histopathological Features

Microscopically, Pagetoid reticulosis exhibits a striking epidermotropic infiltrate of atypical T-cells, which localize within the epidermis in a pattern reminiscent of Paget’s disease. The neoplastic lymphocytes form a dense, band-like arrangement, extending individually or in small clusters between keratinocytes. Large, hyperchromatic lymphoid cells with irregular nuclear contours resemble those seen in mycosis fungoides but display a more pronounced epidermal tropism. Unlike other cutaneous T-cell lymphomas, the infiltrate remains confined to the epidermis and upper dermis.

The epidermis often shows acanthosis and spongiosis, contributing to its resemblance to inflammatory dermatoses. Parakeratosis and hyperkeratosis are common, particularly in long-standing lesions. Despite extensive epidermotropism, Pautrier microabscesses—aggregates of neoplastic lymphocytes within the epidermis—are usually absent, distinguishing it from classic mycosis fungoides. The underlying dermis contains a sparse inflammatory infiltrate but lacks the dense dermal involvement seen in more aggressive lymphoproliferative disorders.

Immunohistochemically, the neoplastic cells exhibit a mature T-cell phenotype, typically expressing CD3, CD4, and CD8, with CD8 positivity more common than in other epidermotropic T-cell lymphomas. T-cell receptor (TCR) gene rearrangements confirm clonality. Loss of pan-T-cell markers such as CD5 or CD7 is frequently observed. The Ki-67 proliferation index is generally low to moderate, reflecting the disease’s indolent nature. CD30 expression is absent, helping differentiate it from primary cutaneous CD30+ lymphoproliferative disorders.

Subtypes

Pagetoid reticulosis has historically been considered a monomorphic entity, but distinct subtypes have been identified. The most recognized classification divides the disease into a localized form—Woringer-Kolopp disease—and a rare disseminated variant.

The localized subtype presents as a solitary, slowly progressive plaque with well-defined borders. It maintains a strictly epidermotropic pattern without systemic involvement, aligning with its indolent nature and favorable prognosis. The disease course is typically stable over many years, with minimal risk of transformation into a more aggressive lymphoma.

The disseminated form, sometimes referred to as Ketron-Goodman disease, is more aggressive, with multiple lesions appearing across different anatomical sites. Unlike the localized variant, these lesions may spread more broadly, raising concerns for systemic progression. Histologically, this subtype exhibits denser infiltrates with more cytologic atypia, sometimes resembling other cutaneous T-cell lymphomas. While still epidermotropic, the infiltrate may extend deeper into the dermis, suggesting a more advanced pathological process. Due to its rarity, definitive prognostic data remains limited, but case reports suggest a more unpredictable disease trajectory.

Diagnostic Markers

Diagnosis relies on histopathological examination and immunohistochemical staining, as its clinical presentation often mimics benign inflammatory dermatoses. A defining feature is the epidermotropic proliferation of atypical T-cells, which immunohistochemistry helps distinguish from reactive lymphocytes.

Neoplastic cells typically express pan-T-cell markers such as CD3 while demonstrating an immunophenotypic profile that differentiates them from other cutaneous lymphomas. CD4 and CD8 expression patterns provide valuable diagnostic insights, as Pagetoid reticulosis often exhibits a predominant CD8+ T-cell phenotype, distinguishing it from mycosis fungoides, which is usually CD4-dominant. Loss of pan-T-cell markers such as CD5 or CD7 further supports a malignant process.

Molecular studies, including T-cell receptor (TCR) gene rearrangement analysis, confirm clonality, reinforcing the diagnosis in ambiguous cases. This molecular test is particularly useful when histopathology and immunophenotyping yield inconclusive results.

Immune Microenvironment

The immune landscape of Pagetoid reticulosis is shaped by interactions between neoplastic T-cells and surrounding cutaneous immune cells. Unlike other cutaneous T-cell lymphomas, which infiltrate the dermis diffusely, Pagetoid reticulosis remains confined to the epidermis. This localization influences the immune response, as keratinocytes and resident Langerhans cells play a role in modulating tumor behavior.

The microenvironment in these lesions lacks significant inflammatory infiltration, contrasting with the dense immune presence in other lymphoproliferative disorders. This relative immune privilege within the epidermis may contribute to the disease’s indolent nature, as the lack of a robust immune response allows neoplastic cells to persist.

Cytokine profiling shows an altered balance between pro-inflammatory and immunosuppressive signals, with elevated IL-15 and TGF-β supporting T-cell survival while dampening immune-mediated clearance. Regulatory T-cells (Tregs) are present in small numbers but appear less suppressive than in more aggressive cutaneous lymphomas.

Expression of immune checkpoint molecules such as PD-1 and CTLA-4 on tumor-infiltrating lymphocytes remains low, suggesting immune exhaustion is not a prominent feature. This contrasts with advanced mycosis fungoides and Sézary syndrome, where PD-1 upregulation is linked to disease progression. The absence of systemic immune dysregulation further supports the localized nature of Pagetoid reticulosis, distinguishing it from disseminated cutaneous lymphomas.