The clinical features of cutaneous lymphadenoma are not specific. Asymptomatic, flesh-colored to erythematous papules or nodules with a domed surface involving the head, neck, or legs are most commonly reported. The tumor is typically diagnosed in young to middle-aged adults, possibly with a slight predominance in men.¹

Generally, cutaneous lymphadenoma is composed of circumscribed but unencapsulated dermal nodules or islands of basaloid cells embedded in a fibrotic to desmoplastic stroma (Fig. 44-1). Epidermal connections are minimal, if present at all. The epithelial lobules are round or irregularly shaped and usually show peripherally located, palisaded basophilic cuboidal cells. Centrally, epithelial cells are larger with eosinophilic cytoplasm, vesicular nuclei, and occasional nucleoli.¹ The tumor lobules usually do not exhibit tumor–stroma clefting as would be seen in basal cell carcinoma. Focal follicular or sebaceous differentiation has been reported, suggesting pilosebaceous derivation, and is supported by the presence of occasional papillary mesenchymal bodies² and an immunohistochemical staining pattern similar to trichoblastoma.³ However, ductal differentiation is also rarely reported,^4,5 although other authors have suggested that intratumoral ducts may represent entrapped normal structures.⁶ The epithelial islands are invariably associated with a brisk lymphohistiocytic infiltrate. Plasma cells are not usually part of the infiltrate. Both within the epithelial and stromal components, small lymphocytes are seen, and within the paler central epithelial component there are frequently scattered large, sometimes multinucleated cells with prominent, eosinophilic nucleoli resembling the Reed–Sternberg cells of Hodgkin lymphoma (Fig. 44-2).¹ The lymphoid infiltrate has been reported to be heavier at the dermal–subcutaneous junction and within the tumor lobules.^2,7 Spongiosis is often prominent among the epithelial nests.

The epithelial component of the tumor may be highlighted with cytokeratin immunohistochemical stains, although recognition of the epithelial nature is rarely problematic. The lymphoid infiltrate has previously been characterized. The lymphocytes are predominantly T cells, with B cells representing a minority of the infiltrate. Further analysis of T-cell subsets has suggested that they are memory and regulatory T cells.⁸ A component of intraepithelial Langerhans cells (CD1a⁺ and S100+) is also usually present. The large, Reed-Sternberg–like cells are decorated by CD30, and have been postulated variably to represent activated lymphocytes⁶ or histiocytes.³

The differential diagnosis of cutaneous lymphadenoma includes clear cell basal cell carcinoma, clear cell syringoma, and lymphoepithelioma-like carcinoma (LELC). In spite of the consistent presence of a dense lymphoid infiltrate, the epithelial nature of the tumor is usually evident and consideration for lymphoma is rarely raised. Basal cell carcinoma may be distinguished from lymphadenoma by the presence of larger tumor cells, tumor–stroma clefting artifact, and brisk mitotic activity and the absence of a desmoplastic “follicular” stroma. Clear cell syringoma demonstrates well-defined ductular differentiation, and, like clear cell basal cell carcinoma, usually lacks an associated prominent lymphoid infiltrate. LELC (discussed later) has a cytologically malignant epithelial component and lacks the CD30⁺ Reed-Sternberg–like cells that may be seen in lymphadenoma.

Spiradenoma classically presents clinically as a painful dermal nodule. There is a predilection for occurrence on the trunk or head and neck, but it may be found on the extremities.

Although origin from the eccrine apparatus or apocrine derivation has not been conclusively settled, the dermal-based tumor typically exhibits clear areas of ductal differentiation. Composed classically of two epithelial cell types—a peripheral rim of small, dense, basaloid cells with hyperchromatic nuclei and central cells with larger, paler nuclei with vesicular chromatin pattern—spiradenomas are also invariably associated with an evenly dispersed infiltrate of inflammatory cells in the center of tumor lobules (Fig. 44-3). The reliability of such finding can be a diagnostic clue as lymphocytes are not classically associated in similar adnexal tumors such as cylindroma.¹¹

The inflammatory cells associated with spiradenoma have been characterized immunohistochemically. CD3⁺ T cells and Langerhans cells (S100 protein and CD1a positive) make up the inflammatory infiltrate, with approximately equally distributed numbers of CD8 and CD4 subsets distributed within the parenchyma of the tumor lobules.¹²

Should the inflammatory infiltrate overwhelm the epithelial elements, the low-power impression of a lobular aggregate of small blue cells could simulate a lymphomatous infiltrate (Fig. 44-4). The unusual occurrence of malignant transformation of spiradenoma and its related hybrid tumor spiradenocylindroma has been described as histologically resembling lymphoepithelial carcinoma (discussed in the next section).¹³

Cutaneous LELC typically presents on the head and neck of older to elderly individuals as a slow-growing papule, plaque, or nodule. Tumors may be flesh-colored or red and clinically mistaken for basal cell carcinoma, Merkel cell carcinoma, or squamous cell carcinoma.^21,22

On microscopic examination, LELC is usually a dermal-based tumor composed of lobules, small nests, or single-cell clusters of cohesive, large, epithelioid but generally poorly differentiated cells (Fig. 44-5). Tumor cells are polygonal with large, chromatin-dense and vesicular nuclei, prominent nucleoli, and often brisk mitotic activity. The epithelioid nature of the tumor cells may be obscured by a florid lymphoid infiltrate that permeates within and around tumor lobules (Fig. 44-6). Evidence of focal trichilemmal keratinization and ductal differentiation has been observed in some cases, leading to speculation that LELC may represent an adnexal tumor rather than a variant of squamous cell carcinoma, although this remains unproven.^14,21,23

Concealed epithelioid tumor cells will be highlighted by epithelial markers such as cytokeratins, epithelial membrane antigen (EMA), or p63 (Fig. 44-7). Some reports indicated staining with high-molecular-weight keratins,^24,25 providing some support for epidermal rather than adnexal derivation. The invariably associated lymphoid infiltrate is composed of a mix of B cells, T cells, and mature plasma cells. A single case report documents the concurrent diagnosis of LELC and cutaneous marginal zone lymphoma in the same specimen, as proven by the demonstration of light-chain restricted plasma cells and immunoglobulin heavy-chain gene rearrangement. The authors hypothesized that the inflammatory infiltrate intrinsic to the LELC may have provided the chronic inflammatory stimuli necessary to induce the development of the low-grade B-cell lymphoma.²⁵

Cutaneous lymphadenoma is a benign adnexal neoplasm exhibiting ductal differentiation. Although often associated with a similarly dense inflammatory infiltrate, the epithelial cells that comprise the tumor nests and lobules of lymphadenoma are typically better delineated, and composed of small-to-medium that lack cytologic features of malignancy.²² Malignant transformation of benign lymphadenoma and spiradenocylindroma has been said to resemble LELC.^1,13

Distinction of primary cutaneous LELC from metastatic lymphoepithelial carcinoma from another site may be accomplished by thorough clinical workup and by detection of EBV within the tumor. Polymerase chain reaction (PCR) or in situ hybridization studies for EBV-encoded RNA (EBER) may be performed on paraffin-embedded tissue blocks.^15,16,18

If the epithelial tumor cells are not appreciated on routine histologic sections, lymphoma and pseudolymphoma may enter the differential diagnosis.²² Astute identification of epithelioid cells and utilization of cytokeratin immunohistochemical stains will facilitate the diagnosis.

Halo nevi are melanocytic nevi surrounded clinically by a rim of depigmentation (a “halo”), which corresponds to spontaneous immune-mediated involution of the lesion. Though possible at any age, halo nevi typically occur in children and adolescents. The nevi, prior to acquisition of the clinical halo, may be congenital or acquired and sometimes clinically atypical or of the Spitz type,³⁰ but are generally small, evenly pigmented, and symmetric. Multiple halo nevi have been reported as occurring concurrent with or subsequent to the diagnosis of melanoma, posited to represent an immune response to melanoma resulting in cross-reactivity with benign melanocytes.³¹ If left alone, halo nevi typically result in an area of clinical depigmentation.³²

In contrast, melanoma with features of regression usually has a markedly atypical clinical appearance. The lesion may be large, asymmetric and irregularly contoured, and variegated in color. Regression in particular is associated with a white-to-gray scar-like discoloration, often described as a “blue-white veil” on dermoscopic evaluation, or with blue-to-gray pepper-like granules.³³ Moreover, melanomas present in an older demographic than halo nevi, and incidence increases with age.

Both halo nevi and regressing melanoma are characterized by melanocytic proliferations with sometimes obscuring lymphocytic inflammation (Fig. 44-8); however, the character of the melanocytic proliferation is different. Benign melanocytic nevi are symmetric, nested populations of melanocytes. Nests of melanocytes within the epidermis are most often found at the tips of rete ridges, and confluent single cells along the junction or upward scatter of melanocytes are lacking. Nests of melanocytes in the dermis display “maturation”; that is, the nests and individual melanocytes decrease in size with further descent into the dermis (Fig. 44-9). Cytologic atypia and mitotic figures are usually not apparent. Melanoma, on the other hand, tends toward a single cell over nested pattern of intraepidermal growth. Melanocytes classically extend above the basal layer in a Pagetoid manner (Fig. 45-10). Invasion into the dermis is characterized by expansile, sheet-like or large nests of cytologically atypical melanocytes. Large cells are present at the base of the lesion (an absence of maturation), and mitotic figures may be evident.

The inflammatory cells that are present in association with benign nevi are thought to account for the clinical halo phenomenon. These inflammatory cells have been found to be cytotoxic, CD8⁺ lymphocytes, although it is interesting that apoptotic or dying melanocytes are seldom appreciated histologically in the evaluation of halo nevi.^32,34 By flow cytometry, a cytotoxic T-cell response has been found to be generated against the melanocytic antigens gp100 and Mart-1 in a regressing nevus.³¹

Similarly, an inflammatory infiltrate in melanoma is typically composed of cytotoxic T cells. Interestingly, expression of major histocompatibility antigens HLA-A, -B, and -C on melanocytes is seen in both regressing melanoma and halo nevi, whereas this expression is absent in noninflamed nevic nests.^34,35 Specifically, the number of resting cytotoxic T cells, characterized by TIA-1 expression, are noted to be increased in melanoma compared to normal skin and benign nevi³⁶; however, TIA-1 expressing lymphocytes appear to make up a smaller percentage of the inflammatory infiltrate with increasing tumor progression; halo nevi were not specifically examined.³⁷ Most recently, a more detailed analysis comparing the immunophenotype of the infiltrate in halo nevi and regressing melanoma was performed. In the largest-size study of its kind to date, the inflammatory infiltrate of 62 melanomas undergoing regression (14 early, 48 late) and 15 halo nevi was characterized.³⁸ This study confirmed that the T cells with a cytotoxic phenotype are found in both halo nevi and regressing melanoma. Interestingly, expression of cytotoxic markers (granzyme and TIA-1) was found in a greater percentage of the infiltrate in halo nevi compared to regressing melanoma. Moreover, the presence of a higher percentage of PD-1 expressing lymphocytes in halo nevi compared to regressing melanoma was hypothesized to represent an equally strong negative regulator of cytotoxic activity in halo nevi, suggesting a balanced immune response in these lesions.³⁸ In contrast, regressing melanoma, particularly the early, inflammatory phase, demonstrated higher numbers of CD123-expressing plasmacytoid dendritic cells (implicated in induction of immune tolerance) than did halo nevi. Early regression was associated with more TIA-1 expressing lymphocytes than late regression, sharing some features of halo nevus, but the presence of a higher CD123-to-TIA-1 ratio in melanoma suggested to the authors an overall less efficient immune response in regressing melanoma than in halo nevi.³⁸

Halo nevi should be distinguished from inflammatory regression of melanoma using criteria as specified earlier. The clinical and cytologic attributes of the lesion typically are sufficient to allow for distinction, although the inflammatory cells may induce reactive cytologic atypia in otherwise benign halo nevi, particularly in variants like Spitz nevi that have a preexisting degree of cytologic atypia.³⁰

On occasion, the associated inflammatory infiltrate may be so dense as to obscure the melanocytic nature of the lesion (Fig. 44-11). In these cases, the lymphohistiocytic infiltrate may be mistaken for an inflammatory dermatosis, cutaneous lymphoid hyperplasia, or even cutaneous lymphoma. Exocytosis of cytotoxic T cells may mimic the epidermotropism and Pautrier microabscesses of cutaneous T-cell lymphoma (mycosis fungoides).³⁹ Residual melanocytes may be mistaken for the large, CD30⁺ lymphoid cells of lymphomatoid papulosis or less likely anaplastic large-cell lymphoma or Hodgkin lymphoma.³⁹ In such cases, application of melanocytic-specific immunohistochemical stains (Mart-1, Melan-A, MiTF, HMB-45, Sox10, S100 protein) should allow for highlighting of residual melanocytes, leading to the correct diagnosis (Fig. 44-12).

Epithelioid hemangioma most often presents clinically as red-to-brown papules, plaques, or nodules and may be single or multiple. A zosteriform distribution has also been reported.⁴¹ The prototypic location is the head and neck, although extremities⁴² and penis⁴³ are other frequently reported sites of occurrence. Extracutaneous lesions are even occasionally reported.⁴⁴ The lesions typically arise in adults with no definitive gender predilection, and may clinically simulate cutaneous lymphoid hyperplasia, arthropod bite reactions, cutaneous lymphoma, or metastasis.⁴⁰

Epithelioid hemangioma is characterized by two dominant components: a vascular proliferation characterized by plump, histiocytic-appearing endothelial cells, and a mixed inflammatory infiltrate that classically contains numerous eosinophils (Fig. 44-13). When the inflammatory component predominates, a lymphoproliferative process may be suspected, so careful attention to the detection of the background vascular component should be sought (Fig. 44-14). The vascular element is composed of a vaguely lobular to nodular proliferation of vessels lined by endothelial cells that have variably been described as plump, histiocytoid, hob-nailed, or epithelioid (Fig. 44-15). In some cases, a small muscular artery or vein demonstrating mural damage may be associated with the vascular proliferation, particularly when the lesions are more deeply seated in the subcutis, again suggesting a relationship to trauma in the development of this entity.⁴³ Intimately associated with the vascular component is a lymphohistiocytic infiltrate with eosinophils, scattered plasma cells, and occasionally, large transformed/activated lymphocytes.⁴² Exceptionally, giant cells with a granulomatous and fibrosing reaction pattern have been reported.⁴⁵ The inflammation tends to be perivascular and periadnexal and spans the dermis, with not infrequent extension to the subcutis. Lymphoid follicles with germinal center formation may be present, and the infiltrate may be more pronounced at the periphery of the lesion and/or at the junction of the dermis and subcutis.⁴²