Extranodal Rosai–Dorfman Disease in the Scrotum of a 13-Month Male (2014)

To the Editor: Rosai–Dorfman disease (RDD), formerly known as sinus histiocytosis with massive lymphadenopathy, is usually characterized by substantial bilateral, painless lymphadenopathy, fever, polyclonal gammopathy, and leukocytosis.1 Extranodal involvement occurs in up to 41% of systemic cases, with skin being the most common site.2 RDD confined only to the skin (primary cutaneous RDD) is rare, with fewer than 40 cases reported in the literature, but has been described in a wide array of anatomic sites.3 Although testicular involvement by RDD has been documented occasionally,4,5 involvement of scrotal skin by cutaneous RDD in an infant has not yet been described in the literature. A 13-month-old white male presented with a several month history of scrotal swelling and bilateral inguinal lymphadenopathy without any associated systemic symptoms. On physical examination, a 2-cm, ulcerated lesion on the right scrotum was appreciated (Fig. 1). The preoperative clinical diagnosis was that of a scrotal ulcer/mass with associated lymphadenopathy, and the mass was subsequently excised without complication.FIGURE 1: Well-circumscribed, ulcerative lesion on right scrotum.Histologic examination revealed a dense dermal infiltrate of histiocytic cells, with ulceration of the overlying epidermis. Most of these cells had abundant lightly eosinophilic cytoplasm, round nuclear contours, and single, distinct nucleoli. Admixed lymphoid aggregates with conspicuous plasma cells and scattered granulocytes were present surrounding the sheets of histiocytes (Figs. 2–4). The histiocytic cells were uniformly strongly positive for S100 protein and CD45 (leukocyte common antigen) and variably positive for CD68 by immunohistochemistry; they were negative for CD1a, smooth muscle actin, and pan-cytokeratin. The S100 protein immunohistochemical stain highlighted numerous emperipoletic histiocytes (Fig. 5). Special stains for fungal and mycobacterial organisms were negative. The morphologic and immunophenotypic features were diagnostic of cutaneous involvement by RDD. Postoperatively, the scrotal mass had not recurred, but the patient demonstrated stable, persistent inguinal lymphadenopathy, which was clinically felt to represent nodal involvement by RDD. Radiographic imaging or tissue diagnosis of the lymph node was not pursued given the lack of systemic symptoms. At last examination, the patient had remained afebrile, was achieving normal developmental milestones, and had no evidence of any additional systemic RDD involvement, other than mild microcytic anemia. He has received no additional therapy and is being followed with observation alone.FIGURE 2: Low-power photomicrograph showing an ulcerated lesion comprised of a dense dermal infiltrate of histiocytic cells.FIGURE 3: Medium-power photomicrograph showing a proliferation of histiocytic cells with abundant, lightly eosinophilic cytoplasm, round nuclear contours, and single, distinct nucleoli. There are also admixed lymphoid aggregates with few scattered plasma cells and granulocytes present surrounding the sheets of histiocytes.FIGURE 4: High-power photomicrograph of the infiltrate highlighting histiocytes showing emperipolesis and surrounding inflammatory cells.FIGURE 5: S100 protein immunohistochemical stain confirms the diagnosis and highlights the emperipolesis.To our knowledge, this is the first reported case in the literature of scrotal skin involvement by RDD in an infant. RDD has 2 recognized forms: systemic and cutaneous. Nodal RDD is often seen in young adults and children with a slight male:female predominance (4:3),6 whereas primary cutaneous RDD is more common in older patients, with a preponderance of cases among females.3,7 Some have proposed that cutaneous RDD represents a distinct clinical subset from nodal RDD, based on these demographic differences and the absence of the systemic abnormalities (e.g., fever, malaise, night sweats, anemia, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia) in most patients with primary cutaneous disease, in contrast to patients with systemic RDD where such abnormalities are common.7 Interestingly, our patient did not report fever, malaise, or night sweats, although at his follow-up visit he was found to have a mild microcytic anemia. Our patient's paucity of systemic clinical or laboratory abnormalities despite persistent lymphadenopathy somewhat blurs the distinction between the 2 forms of RDD. His disease could be considered systemic RDD with extranodal, limited cutaneous disease or primarily cutaneous RDD with secondary regional lymph node involvement. Histologically, RDD classically has a nodular or sheet-like infiltrate of large polygonal histiocytes with large, vesicular, round to oval nuclei and abundant eosinophilic cytoplasm. Helpful clues to the diagnosis of cutaneous RDD, especially in the absence of associated lymphadenopathy, include the presence of abundant pale eosinophilic cytoplasm, identification of the hallmark histologic feature of emperipolesis, and the presence of accompanying lymphoid aggregates and scattered plasma cells.7 Epidermal changes occur in approximately half of cases and include acanthosis, collarette formation, basal layer hyperpigmentation, and ulceration.7 The histiocytes express S100 protein and CD68 and are negative for CD1a, which helps to differentiate these cells phenotypically from Langerhans cells. Although RDD and Langerhans cell histiocytosis are often discussed together because of their shared S100 positivity, the morphologic features are usually sufficient to distinguish between the two entities. Additional entities within the histopathologic differential diagnosis of RDD include infectious etiologies, reticulohistocytoma, xanthogranuloma, and inflammatory pseudotumor (inflammatory myofibroblastic tumor), all of which are almost invariably S100 protein negative. Reticulohistocytoma is a non-Langerhans cell histocytosis that can be occasionally S100 positive, but the prominent “ground-glass” or “two-toned” appearance of the cytoplasm and the lack of an accompanying plasmacytic infiltrate help differentiate this entity.7,8 Infection should be excluded through special stains for organisms and tissue cultures. The etiology of RDD remains unclear. Immune-mediated dysregulation and various infectious agents, including many of the Herpes viruses, Brucella and Klebsiella, have all been proposed as causal or contributing factors,2 but an infectious etiology of RDD has not yet been conclusively identified.9 Regardless of the etiology, RDD is almost always self-limiting and usually spontaneously resolves, although resolution may take years and recurrence is possible. In a series of 22 cases of cutaneous RDD with a median follow-up time of 17 months, approximately one-third of cases still demonstrated persistence of lesions and a few patients had documented new lesions.7 Observation alone is the preferred method of treatment if RDD lesions are not clinically significant mass lesions and do not compromise function of involved organs.2 Treatment (surgical debulking and/or radiotherapy) may be necessary in patients with significant morbidity secondary to lymphadenopathy or organomegaly, such as upper airway obstruction or other vital organ compression.2 In patients with fever >38°C and/or bulky lymphadenopathy, high-dose steroid therapy may afford symptomatic improvement, as long as infection has been excluded. Scrotal involvement by RDD raises a broad clinical differential diagnosis that includes both malignant and infectious disorders, as our case demonstrates. RDD should be considered in the differential diagnosis of cutaneous scrotal lesions and should be included in the histopathologic differential diagnosis of any histiocytic skin lesion occurring in an infant. Biopsy of such lesions is vital to establishing the appropriate diagnosis, and classic histologic features, in conjunction with a characteristic immunophenotype, can distinguish this disease from other cutaneous histiocytic entities.