Rapidly Growing Bleeding Nodule Localized to the Wrist with Scarce Targetoid Papules

To the Editor: Cutaneous pseudolymphoma, often referred to as cutaneous lymphoid hyperplasia (CLH), is a benign reactive lymphoproliferation that closely mimics cutaneous lymphomas in both histopathologic and clinical characteristics. The predominant immunophenotype can vary, allowing for classification into T cell, B cell, and mixed types. This condition may be linked to various factors, including bacterial, viral, and parasitic infections, certain medications, foreign substances such as vaccines, arthropod bites, and ultraviolet radiation.1 We present a case of CLH accompanied by reactive erythema multiforme, which was initially diagnosed as an orf infection. A 30-year-old woman presented with a dark red nodule measuring 15 x 15 mm on the flexor aspect of her left wrist, characterized by areas of crusting and foci of hemorrhage (Fig. 1). Surrounding the nodule and on the palmar surfaces of both hands, scattered erythematous papules were displaying a targetoid appearance (Fig. 2). The patient reported that the nodular lesion appeared 3 weeks ago as a small papule, which gradually enlarged. In addition, a rash developed on both hands 4 days before her visit. She mentioned that she had recently handled raw meat. The patient had no significant comorbidities, was not taking any medications, had no known allergies, and was immunocompetent. A systemic examination revealed normal findings, with no palpable lymph nodes.FIGURE 1.: 15 x 15 mm dark red nodule on the flexor aspect of the left wrist, including crusting regions with foci of hemorrhage and erythematous plaque with targetoid character around the nodule.FIGURE 2.: Scattered erythematous papules with targetoid character on the thenar eminence of the right hand.The complete blood count, comprehensive biochemistry panel, and urinalysis results were all within normal limits. Testing for infectious diseases—including HIV, hepatitis B and C, syphilis, and borreliosis—returned negative results. The primary differential diagnosis identified was orf disease, accompanied by reactive erythema multiforme. The patient was prescribed oral amoxicillin–clavulanate, along with topical mupirocin ointment to prevent secondary infections. In addition, topical mometasone furoate was applied to the areas affected by erythema multiforme. During her visit in the third week, the nodule had reduced in size to 7 x 10 mm, and the scarce targetoid lesions had completely resolved. The patient continued using topical mupirocin ointment for an additional 3 weeks. However, because complete regression was not achieved during the examination in the sixth week, the lesion was excised to exclude the possibility of pyogenic granuloma and amelanotic melanoma. Pathologic examination revealed a diffuse lymphoid proliferation in the upper and middle dermis (top-heavy pattern). Lymphoid cells were of various sizes, not uniform, and no atypia was observed (Figs. 3A, B). Scattered plasmocytes were detected, especially at the bottom of the infiltrate. Immunohistochemical studies showed a T-cell immune profile in lymphoid proliferation (CD2+, CD3+, CD4+, CD5+, CD7+, CD8+; Figs. 4A–C). Infiltration included sparse CD20-positive B cells (Fig. 4D). CD30 immunostaining was negative (Fig. 4E). Ki-67 proliferation index was very low (Fig. 4F). These findings suggested that the proliferation was polyclonal. Therefore, the lesion was diagnosed as T-cell CLH.FIGURE 3.: Histologic appearance of excisional biopsy specimen showing top-heavy pattern dermal lymphoid infiltrate including various sized lymphoid cells with scarce plasmocytes at ×40 magnification (A) and ×400 magnification (B) on H&E-stained slide.FIGURE 4.: Immunohistochemical studies highlight the infiltrate to be composed of CD3+ (A), CD4+ (B), CD8+ (C) T cells (×40). Anti-CD20 highlights scattered B cells admixed within the infiltrate at ×40 magnification (D). Anti-CD30 immunostaining was negative (×40) (E). Ki-67 proliferation index was very low (×200) (F).Cutaneous lymphoid hyperplasia is recognized for its ability to mimic cutaneous lymphomas. However, it is distinct from these malignancies because of its benign and reactive nature, characterized by a polyclonal proliferation of T cells or B cells. Various factors have been proposed as potential triggers for this condition, which can manifest as either localized or disseminated skin lesions.2 Although most cases of CLH are classified as idiopathic, several conditions have been noted in the literature as potential contributors. These include contact dermatitis, lichenoid pigmented purpuric dermatosis, lichen sclerosus et atrophicus, the inflammatory phase of morphea, secondary syphilis, lupus panniculitis, reactions to arthropods, nodular scabies, various viral infections (such as orf, milkmaid's nodule, herpes simplex/zoster, and molluscum contagiosum), tattoo dye, vaccines, trauma, jewelry used in ear piercings (especially gold), acupuncture, as well as infections caused by Borrelia burgdorferi or leishmaniasis, and adverse drug reactions.3 Various approaches have been used to classify CLH. These methods include categorization based on the predominant immunophenotype (T cell, B cell, or mixed), histopathologic growth patterns, etiopathogenesis, and distinct clinical features. Mitteldorf et al proposed a classification system that divides CLH into 4 main groups: nodular type, CLH mimicking mycosis fungoides, and other cutaneous T-cell lymphomas, intravascular type, and a category for the remaining CLHs that do not align with the first 3 groups.4 Among these groups, the nodular type is the most prevalent form, and the current case also demonstrated nodular CLH. Typically, the cutaneous manifestations are not accompanied by systemic symptoms; however, regional lymphadenopathy may occur. Spontaneous remission is a common characteristic of CLH, in contrast to cutaneous lymphomas, which are generally defined by widespread and progressive lesions. A distinctive histopathologic feature of CLH is the top-heavy distribution of dense nodular lymphoid infiltrate, which completely obscures the dermis while minimally extending into the deep dermis and subcutaneous adipose tissue. This infiltrate is usually demarcated from the epidermis by a distinct “grenz zone” and consists primarily of mature small- to medium-sized lymphocytes that largely lack atypical features. Furthermore, immunohistochemical staining is instrumental in differentiating CLH from cutaneous lymphomas and classifying CLH itself. The primary management strategy for CLH involves identifying and eliminating any potential underlying factors, when feasible. First-line treatments include topical or intralesional steroids, topical tacrolimus, topical imiquimod, and oral hydroxychloroquine. Alternative approaches may consist of PUVA, photodynamic therapy using aminolevulinic acid, radiotherapy, laser treatment, or surgical excision.2 The clinical course of CLH can range from spontaneous regression to malignant transformation. Although recurrences may occur after re-exposure to stimuli, the progression of CLH is an exceptional event, often raising questions about a potential misdiagnosis during the initial assessment.3 In cases revealing such transformation, there is an ongoing debate regarding whether these lesions are inherently malignant from the outset or whether malignant transformation occurs over time. Consequently, several authors advocate for the ongoing surveillance of patients to monitor for signs of malignant transformation.3,5 In the current case, the sequential appearance of the fragile nodule and erythema multiforme lesions indicates a likely reactive etiology. The literature has reported instances of erythema multiforme occurring after orf infection.6 Based on the patient's history and clinical presentation, orf infection was considered the primary diagnosis, and we could not rule out the possibility that it triggered the occurrence of CLH. Nevertheless, it is important to note that cases of both orf infection and orf-related CLH typically exhibit a CD30-positive lymphoid infiltrate, which was absent in this instance.4 In addition, the histopathologic examination did not reveal any evidence of viral cytopathic effects. Unfortunately, PCR testing could not be performed, leaving the definitive etiologic factor unresolved. Cutaneous lymphoid hyperplasia (CLH) is a reactive disorder that may be associated with various cutaneous conditions. This case underscores CLH as a potential differential diagnosis for a rapidly enlarging bleeding nodule accompanied by targetoid lesions and outlines the distinctions between CLH, cutaneous lymphomas, and orf disease.