Purely cutaneous rosai-dorfman disease with immunohistochemistry.

BACKGROUND: The cutaneous form of Rosai-Dorfman disease (RDD) is a rare entity that manifests solely with skin papules or nodules and does not present with the usual myriad of symptoms of classical RDD. AIMS: To analyze the most recent publications regarding cutaneous RDD to point out updated, relevant aspects regarding future directions for clinical recognition and management. To identify histopathologic and immunohistochemical findings in skin lesions that permit diagnosis.
MATERIALS AND METHODS: We present a case of a gentleman with a history of multiple lipomas with a new solitary nodule on physical exam; microscopic examination shows the typical findings of RDD with the associated diagnostic immunohistochemical profile, as well as the expected finding of histiocytes engulfing other intact inflammatory cells.
RESULTS: Our patient was managed with surgical excision of the entire lesion, one of the several available treatment options. Long-term follow-up 2 years later did not reveal any complications, recurrences, or new lesions.
CONCLUSION: The diagnosis of cutaneous RDD is differentiated from other histiocytic conditions by the combination of clinical findings accompanied by histopathologic and immunohistochemical confirmation.

What was known?

Rosai-Dorfman disease is an uncommon histiocytic proliferative disorder, which can manifest solely in the skin.

Introduction

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a benign multi-organ non-Langerhans cell histiocytic proliferation that was first described in 1969 by Rosai and Dorfman.[12] The disease most commonly involves the lymph nodes but can be seen in virtually any part of the body; the presentation is usually painless massive bilateral cervical lymphadenopathy. Skin lesions occur in a minority of patients with systemic disease; nonetheless the cutaneous form of RDD, also known as cutaneous sinus histiocytosis, is a rarer entity and is detectable in only 3% of reported cases.[3] The etiology of RDD is unknown, as are the cases with the purely cutaneous form. In some patients, there have been implications of infectious agents including Epstein-Barr virus, human herpesvirus six, parvovirus B19, herpes simplex virus, Brucella, Klebsiella rhinoscleromatis and Nocardia based on positive serology and temporal association.[4] An immunologic reaction triggered by various agents (rather than a single immunologic, infectious, or neoplastic process) has also been proposed.[5]

Patients with cutaneous RDD usually present with a painless mass without lymphadenopathy or systemic symptoms, such as elevated white blood cell count with neutrophilia, fever, erythrocyte sedimentation rate, and/or hypergammaglobulinemia that can be seen in the usual presentation of RDD.[67] Though, one study on 21 lesions states that the skin-limited form shows no specific predilection for a particular location of the body, another more recent study on 25 patients found that the extremities were the most frequently involved site.[89] Characteristic demographics of patients with the cutaneous version of RDD include an older age of onset, female predominance, and a predilection for patients of Asian and white extraction.[4]

Case Report

A 65-year-old white male presented with a singular, 0.8 cm, and slowly growing mass on the right back for evaluation. Grossly, the lesion was a firm, dome-shaped nodule that was brownish-red in color. There was minimal erythema on the underlying skin. There was no history of trauma. The patient reported no associated systemic symptoms, such as fever, weight loss, or malaise. Lymphadenopathy was not appreciated on physical examination. Past medical history of this patient, includes hypertension, steatosis, and over 20 subcutaneous nodules scattered over the forearms, trunk, and neck, which have been surgically excised and diagnosed as lipomas after histopathologic examination. Previous radiologic studies with magnetic resonance imaging demonstrated multiple solitary mobile subcutaneous nodules of fatty tissue measuring a few centimeters in diameter. All pertinent laboratory results including complete blood count with differential and erythrocyte sedimentation rate were unremarkable.

Histologic evaluation shows the dermis occupied by a sheet of confluent histiocytes with scattered neutrophils, lymphocytes, and plasma cells interspersed [Figure 1]. The histiocytes have indistinct cell borders, abundant eosinophilic cytoplasm, low nuclear to cytoplasmic ratio, round vesicular nuclei, and prominent nucleoli. Within some of the histiocytes were intact lymphocytes, plasma cells, and neutrophils that were engulfed by the histiocytes, a process called emperipolesis [Figure 2]. The histiocytes are positive for S-100 [Figure 3] and CD (cluster of differentiation) 68 [Figure 4], and negative for CD1a. The lesion did not penetrate the epidermis or the subcutaneous fat. The lesion was completely resected and follow-up reveals no recurrence or new nodules, and no signs of systemic involvement.

Figure 1

H and E of diffuse histiocytic infiltrate in the dermis, ×100

Figure 2

H and E of histiocytes engulfing other inflammatory cells (emperipolesis), ×400

Figure 3

S-100 stain, positive in the histiocytes, ×400

Figure 4

CD68 stain, positive in the histiocytes, ×400

Discussion

Classic cutaneous RDD presents as firm red to red-brown or xanthomatous macules, papules, nodules or plaques with satellite lesions that are slow growing and frequently multifocal and clustered.[1011] The skin lesions may be variable in size from 1 cm to 30 cm and appear clinically non-specific.[12] On dermoscopy, lesions classically resemble ovoid structures on an erythematous base with multiple yellowish structures in the periphery.[1314]

There has been no documented association between multiple lipomas and RDD. However, panniculitis has been reported in the purely cutaneous form.[15] The soft-tissues remain among the most common extra-nodal sites of involvement for RDD.[16]

Given the fact that the clinical lesions of RDD are relatively non-specific, other histiocytoses, infectious processes, sarcoidosis, and infiltrative disorders should also be considered as part of the differential diagnosis. The diagnosis of cutaneous RDD is differentiated from other histiocytic conditions such as areticulohistiocytoma and xanthogranuloma by the combination of clinical findings accompanied by histopathologic and immunohistochemical confirmation. Although, emperipolesis has been recently described in H syndrome, the clinical findings and age of presentation is not consistent with our case.[17] The key characteristics of this genodermatosis such as hypertrichosis, hyperpigmentation, and indurated patches of skin along with frequent multi-organ associations including hearing loss, hypogonadism, hepatosplenomegaly, short stature, cardiac anomalies, and scrotal masses are not present in our patient thus making it an unlikely diagnosis.[18] Additionally, biopsies of involved skin in H syndrome demonstrate acanthosis and the infiltrate is composed of mast cells as well as histiocytes and plasma cells.[18]

The immunohistochemical profile for this lesion – S-100 positive, CD68 positive, CD1a negative – is pathognomonic for this entity.[19] Though in many cases, the cutaneous histopathology may be very non-specific, and the diagnosis may not be clear until there is evaluation of lymph node or other organ involvement, which places the patient at risk for serious complications.

This disease is considered self-limited due to spontaneous resolution and usually does not require aggressive intervention unless bothersome to the patient or leads to significant functional or physical impairment, such as compression of a vital organ. Yet, there are a few patients reporting refractory or persistent disease.[20] There are numerous treatment modalities for cutaneous RDD, including surgical excision, corticosteroids, thalidomide, cryosurgery, radiotherapy, dapsone, isotretinoin, interferon α, acitretin, and pulsed dye laser; all of these agents have shown varying rates of success.[2122232425] In a clinical and histopathologic study of 25 patients with cutaneous RDD, clinical follow-up in 22 patients indicated that surgical excision was the exclusive effective treatment.[9] Due to the rarity of the disorder, there have been no clinical trials or established guidelines for treatment. Our patient's nodule was completely excised indicating that surgical excision is an effective option for management.

Conclusion

Diagnosis is made by histopathologic examination, where microscopy shows a diffuse infiltrate of typically large, polygonal histiocytes with abundant palely eosinophilic cytoplasm and engulfment of other inflammatory cells. The presence of emperipolesis as observed in this case serves as a very important diagnostic feature and can be highlighted by the S-100 protein stain.

What is new?

The presence of consistent histopathologic and immunohistochemical findings in skin lesions permit diagnosis even in cases without lymph node involvement.