Approach to Cutaneous Lymphoid Infiltrates: When to Consider Lymphoma?

Abstract

Cutaneous lymphoid infiltrates (CLIs) are common in routine dermatopathology. However, differentiating a reactive CLI from a malignant lymphocytic infiltrate is often a significant challenge since many inflammatory dermatoses can clinically and/or histopathologically mimic cutaneous lymphomas, coined pseudolymphomas. We conducted a literature review from 1966 to July 1, 2015, at PubMed.gov using the search terms: Cutaneous lymphoma, cutaneous pseudolymphoma, cutaneous lymphoid hyperplasia, simulants/mimics/imitators of cutaneous lymphomas, and cutaneous lymphoid infiltrates. The diagnostic approach to CLIs and the most common differential imitators of lymphoma is discussed herein based on six predominant morphologic and immunophenotypic, histopathologic patterns: (1) Superficial dermal T-cell infiltrates (2) superficial and deep dermal perivascular and/or nodular natural killer/T-cell infiltrates (3) pan-dermal diffuse T-cell infiltrates (4) panniculitic T-cell infiltrates (5) small cell predominant B-cell infiltrates, and (6) large-cell predominant B-cell infiltrates. Since no single histopathological feature is sufficient to discern between a benign and a malignant CLI, the overall balance of clinical, histopathological, immunophenotypic, and molecular features should be considered carefully to establish a diagnosis. Despite advances in ancillary studies such as immunohistochemistry and molecular clonality, these studies often display specificity and sensitivity limitations. Therefore, proper clinicopathological correlation still remains the gold standard for the precise diagnosis of CLIs.

Keywords: Cutaneous lymphoid hyperplasia; cutaneous lymphoid infiltrates; cutaneous lymphoma; cutaneous pseudolymphoma; simulants of cutaneous lymphomas.

Figure 1

Clinical examples of inflammatory cutaneous lymphoid infiltrates. (a) Sharply demarcated plaques with thick scale in psoriasis; (b) erythematous scaly patches with lichenification in allergic contact dermatitis; (c) drug-induced morbilliform exanthem; (d) hypopigmented, atrophic plaques in lichen sclerosus; (e) red to golden brown macules on the lower extremities in persistent pigmented purpuric dermatitis; (f) hemorrhagic, ulcerated papules in pityriasis lichenoides et varioliformis acuta; (g) erythematous papules and nodules in persistent arthropod bite reaction; (h) atrophic plaque with adherent scale and pigmentary change in discoid lupus erythematosus; (i) subcutaneous red nodules on the face in lupus profundus

Figure 2

Clinical examples of neoplastic cutaneous lymphoid infiltrates. (a) Polymorphous erythematous “wrinkly” patches in mycosis fungoides; (b) scaly erythroderma in Sézary syndrome; (c) clustered erythematous papules and nodules in lymphomatoid papulosis; (d) ulcerated plaque in extranodal natural killer/T-cell lymphoma; (e) rapidly-growing, ulcerated plaques in primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (postmortem image); (f) large, clustered, erythematous nodules in primary cutaneous-anaplastic large cell lymphoma; (g) single erythematous nodule in small-medium pleomorphic CD4+ T-cell lymphoma; (h) large, erythematous, subcutaneous nodule in subcutaneous panniculitis-like T-cell lymphoma; (i) rapidly growing, erythematous to violaceous tumor in diffuse large B-cell lymphoma

Figure 3

(a) Superficial band-like T-cell infiltrate in early mycosis fungoides (H and E, ×20); (b) epidermotropism and lymphocytic atypia in early mycosis fungoides (H and E, ×200); (c) perivascular superficial dermal T-cell infiltrate with acanthosis in psoriasiform dermatitis (H and E, ×20); (d) hyper-parakeratosis, acanthosis, and tortuous capillaries in psoriasiform dermatitis (H and E, ×200); (e) perivascular superficial dermal T-cell infiltrate in spongiotic dermatitis (H and E, ×20); (f) spongiosis and Langerhans cells collections in spongiotic dermatitis (H and E, ×200); (g) dense band-like superficial dermal T-cell infiltrate in lichenoid dermatitis (H and E, ×20); (h) conspicuous interface changes in lichenoid dermatitis (H and E, ×200)

Figure 4

(a) Superficial to deep-dermal, perivascular and/or nodular natural killer/T-cell infiltrate (H and E, ×20); (b) atypical lymphocytes with prominent angiocentricity/ angiodestruction in extranodal natural killer/T-cell lymphoma (H and E, ×400); (c) strong expression by neoplastic lymphocytes in extranodal natural killer/T-cell lymphoma (CD3 epsilon IHC, ×200); (d) strong immunoreactivity in extranodal natural killer/T-cell lymphoma (CD56 IHC, ×400); (e) strong nuclear expression of Epstein–Barr virus-encoded small RNA's in extranodal natural killer/T-cell lymphoma (EBER-ISH, ×400)

Figure 5

(a) Pan-dermal diffuse T-cell infiltrate (H and E, ×20); (b) mixture of small and medium, nonepidermotropic lymphocytes in small-medium pleomorphic CD4+ T-cell lymphoma (H and E, ×200); (c) large atypical cells with prominent nucleoli in anaplastic large cell lymphoma (H and E, ×400); (d) strong expression amongst small and medium T-cells in small-medium pleomorphic CD4+ T-cell lymphoma (CD4 IHC, ×20); (e) positivity restricted to admixed reactive B-cells in small-medium pleomorphic CD4+ T-cell lymphoma (CD20 IHC, ×20); (f) strong expression by sheets of large cells in anaplastic large cell lymphoma (CD30 IHC, ×400); (g) strong immunoreactivity by large cells in extracutaneous anaplastic large cell lymphoma (ALK-1 IHC, ×400)

Figure 6

(a) Panniculitic T-cell infiltrate (H and E, ×20); (b) rimming of adipocytes by atypical lymphocytes in subcutaneous panniculitis-like T-cell lymphoma (H and E, ×400); (c) prominent expression in subcutaneous panniculitis-like T-cell lymphoma (βF1 IHC, ×20); (d) strong immunoreactivity in subcutaneous panniculitis-like T-cell lymphoma (CD8 IHC, ×400); (e) high labeling index, especially among rimming lymphocytes in subcutaneous panniculitis-like T-cell lymphoma (Ki-67 IHC, ×400); (f) strong nuclear expression in gamma-delta T-cell lymphoma (TCRγ IHC, ×400)

Figure 7

(a) Small-cell predominant B-cell infiltrate with germinal centers in cutaneous lymphoid hyperplasia (H and E, ×20); (b) tingible body macrophages in cutaneous lymphoid hyperplasia (H and E, ×200); (c) follicular-dendritic networks in germinal centers of cutaneous lymphoid hyperplasia (CD21 IHC, ×40); (d) immunoreactivity inside a germinal center in cutaneous lymphoid hyperplasia (BCL6 IHC, ×40); (e) superficial and deep small-cell predominant B-cell infiltrate in marginal zone lymphoma (note periadnexal accentuation) (H and E, ×20); (f) peripheral plasma cells and cleaved lymphocytes in marginal zone lymphoma (H and E, ×400); (g) Kappa immunoglobulin light chain restriction in marginal zone lymphoma (Kappa ISH, ×20); (h) absence of lambda expression in marginal zone lymphoma (Lambda ISH, ×20)

Figure 8

(a) Pandermal large-cell predominant B-cell infiltrate (H and E, ×20); (b) medium-sized cleaved lymphocytes (centrocytes) in follicle center lymphoma (H and E, ×400); (c), large round cells with central nucleoli (immunoblasts) in diffuse large B-cell lymphoma (H and E, ×400); (d) expression in follicle center lymphoma (CD20 IHC, ×20); (e) immunoreactivity by most cells in follicle center lymphoma (BCL6 IHC, ×20); (f) atypical follicular dendritic networks in follicle center lymphoma (CD21 IHC, ×20); (g) expression by neoplastic cells in an ulcerated diffuse large B-cell lymphoma (CD20 IHC, ×20); (h) expression by most cells in diffuse large B-cell lymphoma (BCL2 IHC, ×20); (i) high percentage (>50%) of nuclear immunoreactivity in diffuse large B-cell lymphoma (MUM1 IHC, ×20)