Extranodal rosai-dorfman disease presenting as a solitary mass with human herpesvirus 6 detection in a pediatric patient.

In Rosai-Dorfman disease (RDD), exclusive extranodal involvement with lesions limited to the kidneys is very uncommon and has been described only in adult patients. Occasionally, human herpesvirus 6 (HHV-6) has also been detected in RDD tissue samples. We present the case of a 7-year-old boy referred to our center presenting a single solid mass in the right kidney measuring 3.4 cm, detected both on contrast computed tomography and magnetic resonance imaging. Surgical excision was successfully completed, and the pathology report informed characteristic histopathology and immmunohistochemistry features of RDD. Human herpesvirus 6 was detected and amplified by polymerase chain reaction, as well as by immunohistochemistry. We discuss imaging and histology-based differential diagnoses in the pediatric age group. Although RDD is a rare histiocytic disorder of unknown etiology and pathogenesis, the presence of HHV-6 observed in this case supports the possibility of an abnormal immunologic response linked to viral presence.

Soft tissue Rosai-Dorfman disease: 29 new lesions in 18 patients, with detection of polyomavirus antigen in 3 abdominal cases.

Soft tissue Rosai-Dorfman disease (STRDD) is rare, previously reported only as single cases and few series. Simian virus 40 (SV40), a polyomavirus, has been identified in lymphoid processes and has a controversial role in neoplasia etiology. Occasional cytoplasmic pink granular inclusions and nuclear changes led us to explore a viral etiology. Only unpublished STRDD from our files with adequate material, soft tissue location, and diagnostic confirmation were included. Immunohistochemistry and follow-up were obtained. Eighteen STRDD patients, 4 male and 14 female, had 29 lesions; 5 with 2 or more lesions. Ages ranged from 8 to 81 years (mean 42.6 years and median 42.5 years). Soft tissue Rosai-Dorfman disease locations include trunk or proximal extremity (n = 19), distal extremity (n = 5), "abdominal" (n = 3), face (n = 1), and unknown subcutaneous site (n = 1). Sizes ranged from 0.5 to 13.7 cm (median, 2.4 cm). Previous disease included lymphoma, buttocks injection site, diabetes and hypothyroidism, and radiation for chronic dermopathy. No patients had a preceding or concurrent known viral infection; none had lymphadenopathy at present. None were known to be immunocompromised. Soft tissue Rosai-Dorfman disease was rapidly progressing. Initial pathologic diagnosis ranged from Rosai-Dorfman disease or inflammatory pseudotumor to inflammatory malignant fibrous histiocytoma. Grossly STRDDs were multilobulated, tan-yellow, and firm; morphologically, circumscribed, and subcutaneous-based. All had sheets of polygonal histiocytes with abundant pale eosinophilic cytoplasm, emperipolesis, plasma cells, and lymphocytes scattered and within clusters. Focal spindle cell change and mild pleomorphism were each observed in 3 patients; 2 had focal necrosis, none with mitoses. Small granular pink cytoplasmic inclusions and nuclear viral-like changes were observed. By immunohistochemistry, all STRDDs were positive for S100 protein, negative for CD1a, Epstein-Barr virus, and latent membrane protein, yet 3 (all abdominal, 1 multicentric) of the 9 studied were focally positive for cytoplasmic and nuclear SV40 polyomavirus. All were treated by local excision. Follow-up on 14 patients older than 8 to 16 years revealed recurrence in 3 patients with persistent multiple lesions, one with abdominal location. There were no metastases or death from disease. Soft tissue Rosai-Dorfman disease is a rapidly evolving, mostly solitary and nonrecurrent trunk and proximal extremity subcutaneous lesion in middle-aged females. More than one third can have persistent multicentric disease. It is important to recognize STRDD, to separate it from malignancy. Epstein-Barr virus/latent membrane protein was negative but polyomavirus was positive in 3 patients with abdominal STRDD, one with multicentric persistent disease. The relationship of polyomavirus to the evolution of abdominal STRDD should be further explored.

Atypical ocular presentations of Rosai-Dorfman disease.

PURPOSE: To report atypical ocular findings of Rosai-Dorfman disease and to determine association with parvovirus 19. DESIGN: The study is an observational case series of three patients that had atypical ocular presentations of Rosai-Dorfman disease. METHODS: A multicenter, retrospective case series of 3 patients was evaluated for varied ocular complaints, including enlarging epibulbar masses and uveitis. Histologic specimens were examined retrospectively for parvovirus 19 antigen. RESULTS: Patients presented with ocular findings prior to or concurrently with systemic findings, with and without associated lymphadenopathy. Two cases presented with epibulbar masses, one with the mass as the only sign of disease while the other exhibited multinodal involvement with bilateral epibulbar masses and anterior granulomatous inflammation. Parvovirus B19 antibody staining was negative in these cases. The final case exhibited bilateral anterior granulomatous inflammation and choroidal infiltrates. CONCLUSIONS: Ocular findings may be the sole or presenting complaint in Rosai-Dorfman disease prior to recognition of systemic disease and should be considered in the differential diagnosis of epibulbar masses as well as anterior and posterior granulomatous inflammation.

[Rosai-Dorfman disease: clinicopathologic, immunohistochemical and etiologic study of 16 cases].

OBJECTIVES: To study the clinicopathologic features of Rosai-Dorfman disease (RDD), expression of various antigens, human herpes virus type 8 (HHV8), human papillomavirus (HPV)-DNA and Epstein-Barr virus (EBV)-mRNA, and compare the findings with those in the literature. METHODS: The clinicopathologic findings of 16 Rosai-Dorfman disease cases were retrospectively reviewed. Immunohistochemical study for S-100 protein, CD68 (PG-M1), CD163, CD21, CD1a, CD20, CD45RO, CD4, CD8, M-CSF and HHV8 was carried out in 9 of the 16 cases. In-situ hybridization for EBV-mRNA and HPV-DNA was also performed. RESULTS: The male-to-female ratio of the patients was 4.33:1. Amongst the 16 cases studied, 62.5% (10/16) presented nodal RDD, with cervical lymph node predominantly involved. Half of these cases had affected lymph nodes in more than one anatomic site. Extranodal RDD represented 37.5% (6/16) of the cases. The relapse rate of extranodal RDD was higher than that of nodal RDD. Histologically, nodal RDD was characterized by dilated sinuses filled with large polygonal histiocytes which contained lymphocytes and plasma cells. For extranodal lesions, various degrees of stromal fibrosis were seen in association with mixed inflammatory cells (especially plasma cells). The large polygonal histiocytes varied in number and were distributed in clusters or patches. Immunohistochemical study showed that the abnormal histiocytes were strongly positive for S-100 protein. They also expressed CD68, CD163 and M-CSF, but were negative for CD1a, CD21 and HHV8. The lymphocytes in cytoplasm of these histiocytes were positive for both T and B cell markers (with T cell predominance, including a mixture of CD4- and CD8-positive cells). HPV-DNA and EBV-mRNA were not detected by in-situ hybridization. To date, 62 cases of RDD have been reported in mainland China, including 34 cases of nodal RDD and 18 cases of extranodal RDD. The remaining 10 cases involved both lymph nodes and extranodal sites. Compared with overseas reports, RDD occurring in China tended to affect older patients and with slight male predilection. CONCLUSIONS: Rosai-Dorfman disease is relatively rare in China. Pathologic diagnosis of extranodal RDD may be difficult. The demographic data of RDD in China, including age and sex of patients, are different from those in the literature.

Parvovirus B19 detected in Rosai-Dorfman disease in nodal and extranodal manifestations.

Sinus histiocytosis with massive lymphadenopathy (SHML), also designated as Rosai-Dorfman disease (RDD), is a rare benign reactive lymphoproliferative disorder. It is defined by a characteristic histopathology with sinus histiocytosis and haemophagocytosis known as emperipolesis. In histiocytes S100 is strongly expressed, whereas CD1a staining typically is negative. The disease mainly manifests at a single lymph node; however, multilocular and extranodal affection can occur. Causative infectious agents, and virus infections in particular, have repeatedly been suspected, although until now the origin of the disease has been unclear. Four cases of RDD (two nodal sites and two extranodal upper respiratory tract sites) were analysed for parvovirus B19 (B19) infection by immunohistochemistry to detect B19 capsid proteins VP1/VP2. In all the four cases, huge numbers of B19-positive cells were partly detected. The positive cells were identified either as lymphocytes or, in one extranodal case, also as respiratory epithelial cells. This is the first report of B19 infection in RDD tissue, indicating that B19 may be associated with the pathogenesis of SHML.

Parvovirus B19 infection associated with unilateral cervical lymphadenopathy, apoptotic sinus histiocytosis, and prolonged fatigue.

This report describes the case of a 16 year old girl with a history of high fever, prolonged fatigue, and cervical lymphadenopathy of the right side. In addition, the patient showed neutropenia, thrombopenia, and pronounced reticulopenia. Cervical ultrasound showed unilateral hypoechoic lymph nodes up to 23 mm in diameter suspicious for malignant lymphoma. Histology of a cervical lymph node specimen revealed massive nodular histiocytic proliferation and prominent apoptosis without necrosis. Parvovirus B19 was detected by polymerase chain reaction and immunohistochemistry in the lymph node. In summary, this case is an unusual presentation of parvovirus B19 infection. The virus was identified as the potential causative agent of unilateral cervical lymphoma and apoptotic sinus histocytosis, thus broadening the clinicopathological spectrum of parvovirus B19 induced diseases.

Atypical cellular disorders.

Some immunologic diseases are characterized by profound loss or primary dysfunction of a given population of cells. The atypical cellular disorders discussed here all bear some similarities in that abnormal proliferations of lymphocytes and macrophages or dendritic cells result in lymphadenopathy, skin rashes, bone lesions and infiltrations of nearly any other organ system. What are the similarities and the differences between Langerhans cell histiocytosis (LCH), sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease, and Castleman's disease (CD)? Studies on LCH have some advantages since it was described before the others, and organized clinical trials have been done since the 1980s. The understanding of SHML benefited from a registry maintained by Drs. Rosai and Dorfman. CD was described fifty years ago and for one subtype has the most clearly defined etiology (HHV-8 infection) of the three atypical cellular disorders discussed here. In Section I, Dr. Kenneth McClain examines the unanswered question of whether LCH is a malignant clonal disorder or an inflammatory response triggered by aberrant cytokine expression or a virus. Advocates of the malignant proliferation theory rest their case primarily on the following two points: Clonality of the CD1a+ Langerhans cells was demonstrated by analysis of the human androgen receptor in patients with single bone lesions (Low Risk) or multisystem disease including spleen, liver, bone marrow, or lung (High Risk). Although no consistent chromosomal abnormalities have been reported, loss of heterozygosity (LOH) has been defined by comparative genomic hybridization. Those in the "inflammatory response" camp note that non-clonal proliferation of Langerhans cells in adult pulmonary LCH also have LOH by the same method. The pathologic cells have not been successfully grown in culture or immune-deficient mice and don't have a "malignant" morphology. While the basic scientific arguments continue, important advances in the treatment of LCH have been made by international collaborations of the Histiocyte Society. Risk groups have been clearly defined and the response to therapy after the initial 6 weeks is known to be the strongest prognostic variable for outcome. In Section II, Dr. Yasodha Natkunam reviews the features of SHML, which most often presents as painless cervical lymphadenopathy, although many patients can have extranodal involvement as well. These sites include the skin, respiratory tract, bone, lung, gastrointestinal tract, and brain. The diagnosis rests on finding intact lymphocytes in the cytoplasm of activated macrophages as well as accumulation of mature plasma cells. Hemolytic or non-hemolytic anemias, hypergammaglobulinemia, and elevated erythrocyte sedimentatin rate (ESR) are often found with SHML. An intriguing finding of human herpesvirus (HHV)-6 viral proteins in SHML has been reported in several patients, but needs further study. SHML associated with lymphoproliferations triggered by defects in apoptosis are discussed since this mechanism may provide a clue to the etiology. Therapy for SHML varies greatly in reported case series. Many patients have spontaneous regression or resolution after surgical removal of isolated node groups. Others with systemic involvement may benefit from chemotherapy, but no clinical trials have been done. In Section III, Dr. Steven Swerdlow clarifies key features of the four types of CD. Localized cases are divided into the hyaline vascular type and plasma cell type. Both are usually cured by surgical excision and have symptoms mainly of a mass lesion, although the latter often also has constitutional symptoms. The two types are distinguished largely by the nature of the follicles and the number of interfollicular plasma cells. Interleukin (IL)-6 expression is increased in the plasma cell type. Multicentric CD of the plasmablastic type is most often found in HIV-positive patients with coincident HHV-8 infection. Many have lymphomas or Kaposi sarcomas. Other cases of multicentric CD are also most like the plasma cell type, however, with disseminated disease and constitutional symptoms. A wide variety of anti-neoplastic drugs, radiation therapy, anti-IL-6 and rituximab or atlizumab have been used with varying success in patients with multicentric CD. Clinical trials are needed for SHML and CD and registration of adult and pediatric patients on current LCH trials are encouraged.

Cutaneous Destombes-Rosai-Dorfman disease: absence of detection of HHV-6 and HHV-8 in skin.

BACKGROUND: We report three new cases of cutaneous Destombes-Rosai-Dorfman disease (DRDD). Two were skin-limited, and one was associated with systemic involvement. In all cases typical large S100 positive macrophages with emperipolesis were present, but different patterns were seen. A viral etiology has long been suspected in DRDD. METHODS: Thus, all cases were investigated for presence of HHV-6 major capsid protein gene by polymerase chain reaction (PCR), and for presence of HHV-8 latency-associated nuclear antigen 1 by immunohistochemistry. RESULTS: All results were negative. HHV-6 antibody tests were positive for IgG but not for IgM in one case. With regard to HHV-6, previous studies supplied inconclusive results while, to our knowledge, HHV-8 has never been investigated in DRDD. CONCLUSION: This study suggests that HHV-8 is not involved in the pathogenesis of cutaneous DRDD. However, this should be confirmed by further studies. We can postulate three hypotheses in regard to HHV-6 role in DRDD pathogenesis: 1) its presence in lesionnal tissues is fortuitous, 2) HHV-6 plays a role in promoting more aggressive diseases and 3) various causes, including HHV-6, are implicated in the pathogenesis of DRDD.

Sinus histiocytosis confined to the skin. Case report and review of the literature.

Sinus histiocytosis with massive lymphadenopathy is an uncommon disease affecting individuals of either sex and of all ages and ethnic backgrounds. We present a case of sinus histiocytosis confined to the skin in a 65-year-old woman whose diagnosis was coincident with herpes simplex virus infection and polybacterial urinary infection, both asymptomatic. The polymerase chain reaction for herpes simplex virus and human herpesvirus-6 from involved skin was negative. We review previously published cases of sinus histiocytosis limited to the skin.