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This fascinating disorder is also known as Sinus Histiocytosis with Massive Lymphadenopathy. It commonly presents as massive, painless, bilateral lymph node enlargement in the neck with fevers. Most cases occur in the first or second decade of life and have a predilection for blacks. Rarely sites other than the lymph nodes can be involved including the central nervous system, eyes, upper respiratory tract, skin, and head and neck region. Interestingly, the spleen and bone marrow have been spared. These extranodal cases occur in up to 25% of cases. However, in all nodal cases, at least 43% have at least one site of extranodal disease. The association is dependent upon the site of the extranodal disease. For example, all patients with salivary gland involvement had nodal disease while only 50% of patients with central nervous system disease have nodal disease.

Some cases have responded to chemotherapy but many times the disease undergoes spontaneous resolution. In others, an insidious course develops for years or decades. This is more common in the extranodal cases.

The cause is still unknown although a viral etiology is suspected. Molecular studies have found no evidence of clonal rearrangement implying that this disease is a reactive rather than neoplastic condition.


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SYNONYMS Sinus Histiocytosis with Massive Lymphadenopathy
Destombes-Rosai-Dorfman disease
INCIDENCE Very rare, probably less than 1000 cases reported in the literature



Rosai-Dorfman disease and generalized AA amyloidosis: a case report.

Rocken C, Wieker K, Grote HJ, Muller G, Franke A, Roessner A.

Institute of Pathology and Department of Haematology and Oncology, Otto-von-Guericke-University, Magdeburg, Germany.

Hum Pathol 2000 May;31(5):621-4 Abstract quote

We report on a patient who, at 31 years of age, was found to suffer from sinus histiocytosis with massive lymphadenopathy (SHML; Rosai-Dorfman disease) with nodal and extranodal involvement as described previously.

Five years later the patient presented with nephrotic syndrome caused by a generalized AA amyloidosis, and he subsequently died from pulmonary thromboembolism owing to renal vein thrombosis. Retrospective analysis of serum levels of C-reactive protein (CRP) showed that during the last 3 years before his death, he had a persistently elevated CRP level ranging from 73 to 161 mg/L, despite antiinflammatory treatment with prednisolone, methotrexate, or 6-mercaptopurine.

These figures indicate that the patient was probably suffering from a permanent acute phase response which, in the absence of any other evidence of a chronic inflammatory disease which commonly causes AA amyloidosis, was most likely owing to SHML.


Rosai-Dorfman disease complicated by autoimmune haemolytic anaemia: case report and review of a multisystem disease with cutaneous infiltrates.

Grabczynska SA, Toh CT, Francis N, Costello C, Bunker CB.

Department of Dermatology, Chelsea Hospital, Fulham Road, London SW10 9NH, UK.

Br J Dermatol 2001 Aug;145(2):323-6 Abstract quote

We report a patient with sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) who presented with widespread nodal and extranodal involvement affecting the skin, orbits and nasal sinuses, complicated by the development of autoimmune haemolytic anaemia.

The aetiology and pathogenesis of this multisystem disorder are unknown but are thought to represent a reactive histiocytic process to an infective agent rather than a neoplastic or other primary condition. Prognosis is generally good but clinical or laboratory evidence of immune dysfunction tends to predict a poorer outcome.

We describe the clinical course of the patient and review the literature on this disease.

Histologic Features of Sinus Histiocytosis With Massive Lymphadenopathy in Patients With Autoimmune Lymphoproliferative Syndrome.

Maric I, Pittaluga S, Dale JK, Niemela JE, Delsol G, Diment J, Rosai J, Raffeld M, Puck JM, Straus SE, Jaffe ES.

From the *Hematopathology Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD; daggerLaboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD; double daggerClinical Pathology Department, Clinical Center, National Institutes of Health, Bethesda, MD; section signINSERM U563, Departement d'Oncogenese et Signalisation dans les Cellules Hematopoietiques, Hopital Purpan, Toulouse Cedex, France; parallelDepartment of Pathology, National Cancer Institute Milan, Italy; and paragraph signGenetics and Molecular Biology Branch, National Human Genome Research Institute, Bethesda, MD. Dr. Diment's current affiliation is Department of Pathology, Kaplan Medical Center, Rehovot, Israel.
Am J Surg Pathol. 2005 Jul;29(7):903-911. Abstract quote

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder associated with defects in Fas-mediated apoptosis, characterized most often by childhood onset of lymphadenopathy, splenomegaly, hypergammaglobulinemia, and autoimmune phenomena. Children with sinus histiocytosis with massive lymphadenopathy (SHML) have a somewhat similar clinical phenotype in which prominent adenopathy also is associated with hypergammaglobulinemia, and autoimmune phenomena are reported in 10-15% of cases.

We observed histopathological features of SHML in the lymph nodes of some of our ALPS patients, further suggesting an association between these two disorders. We, thus, reviewed the lymph nodes from 44 patients ALPS type Ia, all of whom were confirmed to have germline mutations in the TNFRSF6 gene encoding Fas (CD95/Apo-1). Eighteen of 44 (41%) patients had a histiocytic proliferation resembling SHML. The affected patients included 15 males and 3 females ranging in age from 11 months to 30 years at the time of the LN biopsy. The lymph nodes contained S-100+ histiocytes with characteristic nuclear features of SHML, and showed evidence of emperipolesis in both hematoxylin and eosin (H and E) and immunostained sections. The extent of the histiocytic proliferation was variable, being confluent in 2 cases, multifocal in 13, and only evident as isolated SHML-type histiocytes in 3. In lymph nodes without confluent SHML changes, increased numbers of CD3CD4CD8 (double negative) alphabeta T-cells, also negative for CD45RO, a feature of ALPS, could be identified in the paracortex. Furthermore, because SHML shares many clinical features with ALPS, we sought evidence of ALPS in sporadic SHML. We attempted to sequence TNFRSF6 DNA from archived tissue of 14 cases of Rosai-Dorfman disease. Full sequencing of the gene was successful in 4 of the cases; no mutations were identified. Nevertheless, our observations suggest that histologic features of SHML are part of the pathologic spectrum of ALPS type Ia.

It remains to be determined if some cases of apparently sporadic SHML may be associated with heritable defects in Fas-mediated apoptosis.

Rosai-Dorfman disease (extranodal sinus histiocytosis) in a patient with HIV.

Perry BP, Gregg CM, Myers S, Lilly S, Mann KP, Prieto V.

Division of Otolaryngology-Head and Neck Surgery, Duke University Medical Center, Durham, North Carolina, USA.

Ear Nose Throat J 1998 Oct;77(10):855-8 Abstract quote

Rosai-Dorfman disease, or sinus histiocytosis with massive lymphadenopathy (SHML), is a rare histiocytosis of unknown etiology that most commonly involves the cervical lymph nodes. Extranodal involvement occurs in 30-40% of cases, most often in the head and neck. Characteristic histologic findings include emperiopolesis (engulfment) of lymphocytes and S-100 protein positivity. Treatment of Rosai-Dorfman disease is unnecessary unless the disorder becomes life- or organ-threatening, since the disease will resolve spontaneously in most patients.

We present what, to the best of our knowledge, is the first reported case of Rosai-Dorfman disease limited to the skin in a patient infected with human immunodeficiency virus. SHML is described and diagnostic and therapeutic measures are reviewed.


Morphological, ultrastructural, and genetic characterization of an unusual T-cell lymphoma in a patient with sinus histiocytosis with massive lymphadenopathy.

Koduru PR, Susin M, Kolitz JE, Soni M, Teichberg S, Siques MJ, Sun T, Amorosi E, Budman DR.

Department of Laboratories, North Shore University Hospital-Cornell University Medical College, Manhasset, New York 11030.

Am J Hematol 1995 Mar;48(3):192-200 Abstract quote

Sinus histiocytosis with massive lymphadenopathy (SHML) is a rare benign disease of unknown etiology. It is rarely associated with malignant lymphoma.

This report documents the first case of a T-cell lymphoma, which developed in a patient with a 10-year history of SHML. The disease was complicated by hypereosinophilia and massive retroperitoneal lymphadenopathy. Histological examination of a cervical lymph node biopsy during the terminal phase identified a lymphoma composed of cells with morphological plasmacytoid features. Ultrastructurally, the tumor cells showed poorly developed cytoplasm, nuclei with peripheral chromatin clumping, and inconspicuous nucleoli. Cytogenetic studies showed two related clones. On immunohistochemical staining tumor cells were positive with monoclonal antibodies (mAb) CD3 and CD45RO. Southern blotting analysis identified clonal rearrangements in the T-cell receptor (TCR) alpha, beta and gamma genes.

Thus, T-cell lineage of the tumor cells was established. In situ hybridization of interleukin-2 (IL-2) and interleukin-5 (IL-5) cDNA probes on tissue sections identified the synthesis of IL-5 by the eosinophils, suggesting an autocrine pathway of eosinophilopoiesis leading to hypereosinophilia in this patient.

Sinus histiocytosis with massive lymphadenopathy and malignant lymphoma involving the same lymph node: a report of four cases and review of the literature.

Lu D, Estalilla OC, Manning JT Jr, Medeiros LJ.

Division of Pathology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.

Mod Pathol 2000 Apr;13(4):414-9 Abstract quote

Sinus histiocytosis with massive lymphadenopathy (SHML), also known as Rosai-Dorfman disease, is a disorder of unknown cause. Rarely, patients with SHML also have malignant lymphoma, usually involving anatomic sites different from those involved by SHML

We report four patients in whom SHML and malignant lymphoma were identified in the same lymph node biopsy specimen. The SHML in each case was present as a small focus, less than 1 cm. Immunohistochemical studies showed that the abnormal histiocytes were positive for S-100 and negative for CD1a. The malignant lymphomas included two cases of follicular lymphoma and two cases of Hodgkin's disease, nodular lymphocyte predominant type. The presence of SHML in these patients did not impact clinical decisions, and there was no evidence of SHML elsewhere.

Thus, the presence of focal SHML associated with malignant lymphoma in these cases was an incidental histologic finding that seems not to have had any clinical significance.



Evidence for a polyclonal nature of the cell infiltrate in sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease).

Paulli M, Bergamaschi G, Tonon L, Viglio A, Rosso R, Facchetti F, Geerts ML, Magrini U, Cazzola M.

Department of Human Pathology, University of Pavia, Italy.

Br J Haematol 1995 Oct;91(2):415-8 Abstract quote

Sinus histiocytosis with massive lymphadenopathy (SHML), or Rosai-Dorfman disease, is rare histiocytic disorder of known origin which shares several cell markers with Langerhans' cell histiocytosis (LCH). Although Rosai-Dorfman cells exhibit an aberrant immunophenotype, the indolent clinical course of SHML suggests a reactive disorder rather than a neoplastic process. Until recently this was prevailing opinion concerning LCH also, but recent studies have detected clonal histiocytes in all forms of this latter condition, which is therefore considered a clonal neoplastic disorder with highly variable biological behaviour.

To determine whether the histiocytic proliferation in SHML is polyclonal or clonal we used X-linked polymorphic loci to assess clonality in lesional tissues in two women. Polymorphic regions of the human androgen receptor (HUMARA) locus were amplified by polymerase chain reaction (PCR) analysis.

The HUMARA locus was informative in both cases and, following digestion with methylation-sensitive enzymes, typical polyclonal X-inactivation patterns were observed. Since abnormal cells accounted for > 90% lesional tissue cells, we conclude that Rosai-Dorfman histiocytic proliferation was polyclonal in the women studied.


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

N. Ortonne
A. M. Fillet2, H. Kosuge2, M. Bagot3, C. Frances4 and Janine Wechsler

J Cutan Pathol 2002;29:113-118 Abstract quote

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 capcid protein gene by polymersae 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 agressive diseases and 3) various causes, including HHV-6, are implicated in the pathogenesis of DRDD.


Sinus histiocytosis with massive lymphadenopathy: evidence for its relationship to macrophages and for a cytokine-related disorder.

Middel P, Hemmerlein B, Fayyazi A, Kaboth U, Radzun HJ.

Department of Pathology, Georg August University of Gottingen, Germany.

Histopathology 1999 Dec;35(6):525-33 Abstract quote

AIMS: Sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease is a rare histiocytic disorder of unknown origin. Immunophenotypically the histiocytes of SHML express intensively the S100 protein and in addition a panel of macrophage-associated antigens. Their exact relationship to either monocytes/macrophages or immune accessory dendritic cells is, however, still controversial.

METHODS AND RESULTS: In this report recurrent nodal and extranodal manifestations of SHML of a 70-year-old patient were analysed by differential phenotyping using a panel of monoclonal and polyclonal antibodies to macrophage and immune accessory dendritic cell related antigens and by applying nonradioactive in-situ hybridization.

CONCLUSIONS: We conclude that stimulation of monocytes/macrophages via macrophage colony stimulating factor (M-CSF) leading to immune suppressive macrophages represents a main mechanism for the pathogenesis of SHML. The study further provides evidence for the monocyte/macrophage but not dendritic cell differentiation of SHML histiocytes.


Laboratory Markers  
Serum electrophoresis
Majority have polyclonal elevation of IgG though there are 4 documented cases of monoclonal gammopathy
Erythrocyte sedimentation rate
Elevated in 88.5% of cases


Extranodal rosai-dorfman disease involving the bone marrow: a case report.

Division of Pathology, City of Hope National Medical Center, Duarte, CA 91010.


Am J Surg Pathol. 2006 Sep;30(9):1189-92. Abstract quote

Sinus histiocytosis with massive lymphadenopathy (SHML), also known as Rosai-Dorfman disease, is a very rare disorder of unknown etiology. Although classical SHML usually presents as massive, painless, bilateral neck lymph node enlargement, approximately 25% to 40% of SHML cases described to date present in extranodal organs or tissues, such as skin, upper respiratory tract, and bone etc. However, bone marrow as a site of initial presentation by SHML has not been described since the disease was initially recognized in 1969.

Here, we report the first case of bone marrow involvement by extranodal SHML, which occured in a 73 year-old man with a history of refractory idiopathic thrombocytopenia purpura. The bone marrow biopsy demonstrates the distinctive and characteristic morphologic and immunophenotypic features of extranodal SHML.
CNS J Neurosurg 1984; 60:850-852

Sinus histiocytosis with massive lymphadenopathy: a case of multiple dural involvement.

Sakai K, Koike G, Seguchi K, Nakazato Y.

Department of Neurosurgery, Shinshu University School of Medicine, Matsumoto, Japan.

Brain Tumor Pathol 1998;15(2):63-9 Abstract quote

An exceptional case of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) arising from the meninges in a 60-year-old Japanese man is presented.

Computerized tomographic scans and magnetic resonance images demonstrated well-circumscribed tumorous lesions that were homogeneously enhanced with contrast medium. Systemic examination revealed no abnormalities except for a cervical lymphadenopathy and diabetes mellitus. Microscopic examination of the resected specimens showed proliferated histiocytosis and infiltration of plasma cells and lymphocytes. The histology was characterized by the presence of histiocytes demonstrating lymphophagocytosis and immunoreactivity for S-100 protein staining. Immunohistochemical studies and electron microscopy were useful in confirming the diagnosis. The clinical and histopathological features of this disease are discussed.

Rosai-Dorfman Disease Isolated to the Central Nervous System: A Report of 11 Cases

Jo-Ann W. Andriko, etal.

Mod Pathol 2001;14:172-178 Abstract quote

Sinus histocytosis with massive lymphadenopathy, also known as Rosai-Dorfman Disease (RDD), is an idiopathic histiocytic proliferation affecting lymph nodes. Although extranodal involvement has been reported in diverse sites, central nervous system (CNS) manifestation, particularly in the absence of nodal disease is uncommon.

We report 11 cases of RDD primary to the CNS without evidence of other sites of involvement. The cases included 7 males and 4 females ranging in age from 22 to 63 years (mean: 41 y). The patients presented with headaches, seizures, numbness, or paraplegia. Eight cases involved the cranial cavity and three cases, the spinal canal. Lesions were most often extra-axial and dura based. Only one presented in the CNS parenchyma.

Histologically, the lesions consisted of variable numbers of pale-staining histocytes with emperipolesis often overshadowed by extensive lymphoplasmacytic infiltrates and fibrosis in the background. Special stains for organisms were negative. By immunohistochemical analysis, the characteristic histiocytes were positive for S100 protein and CD68 and negative for CD1a.

Treatment consisted of surgical biopsy or excision.

Follow-up, available for 10 cases with intervals ranging from 5 days to 42 months (mean: 15 mo), disclosed one patient dying of operative complications 5 days after biopsy and nine patients with no evidence of disease progression

RDD should be considered in the differential diagnosis of inflammatory lesions of the CNS. Our study suggests that this entity may have been misdiagnosed in the past as plasma cell granuloma or inflammatory pseudotumor.

A report of intracranial Rosai-Dorfman disease with literature review.

Wu M, Anderson AE, Kahn LB.

Department of Pathology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, NY 11040, USA.

Ann Diagn Pathol 2001 Apr;5(2):96-102 Abstract quote

Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy), is a rare benign histiocytic proliferative disorder. Over 650 cases have been reported since 1969.

To the best of our knowledge, there have been only 31 cases with central nervous system involvement reported in the literature. Intracranial disease usually presents clinically and radiologically as a "meningioma". It can be misdiagnosed as a nonspecific inflammatory process because of the atypical histologic features of Rosai-Dorfman disease occurring in a non-nodal location. Familiarity with such atypical histologic features and appropriate use of immunohistochemical stains is required for a definitive diagnosis of central nervous system Rosai-Dorfman disease.

We report such an intracranial lesion with other extranodal sites of involvement with a 5-year follow up and a review of previously reported cases.

Meningeal Rosai-Dorfman disease: report of three cases and literature review.

Kitai R, Llena J, Hirano A, Ido K, Sato K, Kubota T.

Department of Neurosurgery, Fukui Medical School, Matsuoka Yoshida, Japan.

Brain Tumor Pathol 2001;18(1):49-54 Abstract quote

Rosai-Dorfman disease is a well-recognized clinicopathological entity, which in rare cases affects the central nervous system, where it mimics meningioma.

We describe three cases and review the literature. Histological and immunohistochemical confirmation is essential for definitive diagnosis. In addition to emperipolesis (lymphophagocytosis), reactivity for S-100 and CD68 and nonreactivity for CD-la immunostaining are characteristic features of this histioproliferative disease. In contrast to meningioma, this tumor usually occurs in young males and infiltrates the brain parenchyma.

Extranodal Rosai-Dorfman disease of the kidney and coexistent poorly differentiated prostatic adenocarcinoma.

Harik L
Nassar A.

Department of Pathology, Emory University Hospital, School of Medicine, Atlanta, Ga 30322, USA.


Arch Pathol Lab Med. 2006 Aug;130(8):1223-6 Abstracte quote

We present a case of a patient who was initially diagnosed with poorly differentiated prostatic adenocarcinoma on prostate needle core biopsy. Upon staging workup, a computed tomographic scan showed a 9-cm left renal mass involving mainly the pelvicalyceal system.

Positron emission tomographic scan showed increased uptake in para-aortic, paracaval, and retrocaval lymph nodes suspicious for metastatic disease. Left nephrectomy revealed involvement with extranodal Rosai-Dorfman disease. Lymphadenectomy revealed metastatic prostatic adenocarcinoma; however, the lymph nodes did not show evidence of Rosai-Dorfman disease.

Isolated involvement of the kidney by Rosai-Dorfman disease is very rare. The combination of prostatic adenocarcinoma and isolated extranodal Rosai-Dorfman disease of the kidney makes this case unique.

Intraoral presentation of Rosai-Dorfman disease: A case report and review of the literature.

Kademani D, Patel SG, Prasad ML, Huvos AG, Shah JP.

Memorial Sloan-Kettering Cancer Center.

Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002 Jun;93(6):699-704 Abstract quote

Rosai-Dorfman disease, or sinus histiocytosis with massive lymphadenopathy, is an unusual clinical entity. It classically presents with massive cervical lymphadenopathy, but atypical presentations have been described in the absence of nodal involvement, making diagnosis difficult.

We report a case that presented with isolated involvement of the maxillary alveolus and discuss the diagnostic dilemmas and approaches to management in patients with atypical clinical features.

Cutaneous Rosai-Dorfman Disease: A Clinical and Histopathologic Study of 25 Cases in China.

*Department of Pathology, Cancer Hospital, Fudan University, Shanghai, P.R. China daggerDepartment of Pathology, First People's Hospital, Shanghai Jiaotong University, P.R. China.


Am J Surg Pathol. 2007 Mar;31(3):341-350. Abstract quote

Cutaneous Rosai-Dorfman disease (CRDD) is a rare proliferative disorder of histiocytes with unknown etiology, broadly different from systemic Rosai-Dorfman disease.

We present the largest series of CRDD, describing the clinical manifestation, histopathology, immunohistochemistry, and follow-up course of 25 cases in China.

Clinically, 39 skin lesions in 25 patients were divided into 3 main types: papulonodular type (79.5%), indurated plaque type (12.8%), and tumor type (7.7%). Extremities were the most frequently involved, followed by trunk and face. None of the patients was found to have visceral organ involvement or lymphadenopathy.

Microscopically, CRDD was characterized by scattering, clusters or sheets of large polygonal histiocytes intermingled with a florid, mixed inflammatory infiltrate. The most important feature was emperipolesis, which can be highlighted by S-100 protein stain. Patch and bandlike infiltrate of numerous mature plasma cells around glands and vessels was a constant finding in all lesions. Neutrophils existed in all cases to a variable degree with 2 cases forming microabscess. Four cases were remarkable for fibrosis, and xanthomatous change was observed in 2 cases. Coexistence of localized Langerhans cell histiocytosis and CRDD was interestingly found in case 7, which was evidenced by CD1a stain.

Clinical follow-up in 22 patients, ranging from 2 to 55 months, indicated that surgical excision was the exclusive effective treatment for CRDD. Partial or complete spontaneous remission was achieved in 7 patients within 6 to 55 months. Owing to its favorable outcome, CRDD should be differentiated from a variety of benign and malignant lesions.

Recognition of its wide clinical spectrum and histologic features combined with S-100 protein stain can help to establish the correct diagnosis.

Histologic features of cutaneous sinus histiocytosis (Rosai-Dorfman disease): study of cases both with and without systemic involvement.

Chu P, LeBoit PE.

Department of Dermatology, School of Medicine, University of California, San Francisco 94143-0506.

J Cutan Pathol 1992 Jun;19(3):201-6 Abstract quote

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) is a systemic proliferation of cells that resemble the sinus histiocytes of lymph nodes. Whereas initial reports highlighted the often striking cervical adenopathy, more than 40% of patients have extranodal involvement. Cutaneous lesions are the most common form of extranodal disease, but cases that present as cutaneous disease without lymph node involvement are rare.

We examined biopsies from three patients with cutaneous lesions of sinus histiocytosis, none of whom had detectable systemic involvement, and compared them to those of two patients whose lymph nodes were involved by the disease. The histology of skin lesions in all five cases showed dense nodular or diffuse infiltrates of "histiocytes," emperipolesis of lymphocytes, neutrophils, and plasma cells. "Histiocytes" were present in lumens of dilated lymphatics. At the peripheries of the lesions were lymphoid aggregates and thick-walled vessels surrounded by plasma cells. Staining with anti-S-100 protein antibody showed marked cytoplasmic positivity in the "histiocytes" in each case. The only features that differed among the two groups were the presence of pseudoepitheliomatous hyperplasia and infiltrates of eosinophils in one case in which the disease was limited to the skin.

We believe that cutaneous sinus histiocytosis can be specifically diagnosed by skin biopsy. Because cutaneous sinus histiocytosis may be unfamiliar to general pathologists, dermatopathologists, and dermatologists, cases limited to the skin may be under-recognized.

Cutaneous Rosai-Dorfman disease presenting as a suspicious breast mass.

Mac-Moune Lai F, Lam WY, Chin CW, Ng WL.

Department of Anatomical & Cellular Pathology, Chinese University of Hong Kong, Shatir.

J Cutan Pathol 1994 Aug;21(4):377-82 Abstract quote

Cutaneous Rosai-Dorfman disease in a male patient presented as a clinically malignant left breast mass. The intra-operative frozen section indicated a benign inflammatory lesion and a simple excision was performed. The disease was apparently limited to the skin and subcutis of the left breast with no lymph nodes or other organs involvement. While the lesion demonstrated the characteristic morphology of Rosai-Dorfman disease, the diagnosis of granulomatous mastitis, epithelioid sarcoma and other cutaneous xanthohistiocytic proliferations were considered. In the absence of lymphadenopathy, a high index of diagnostic awareness is required to recognize the uncommon, solitary cutaneous Rosai-Dorfman disease.

Cutaneous sinus histiocytosis (Rosai-Dorfman disease) presenting clinically as vasculitis.

Stefanato CM, Ellerin PS, Bhawan J.

Dermatopathology Section, Department of Dermatology, Boston University School of Medicine and Department of Dermatology, Tufts University School of Medicine.

J Am Acad Dermatol 2002 May;46(5 Pt 1):775-58 Abstract quote

The cutaneous variant of Rosai-Dorfman disease is a rare benign lymphoproliferative disorder that occurs without lymphadenopathy or internal organ involvement.

We present a 55-year-old woman with a diffuse exanthematous eruption that evolved into pruritic papulopetechial and purpuric lesions on the back and lower extremities, diagnosed clinically as a vasculitis. The patient's lesions cleared spontaneously with no recurrence. Histopathologic examination showed a dense dermal nodular lymphohistiocytic infiltrate with occasional eosinophils, plasma cells, and neutrophils and with numerous extravasated red blood cells. The large, foamy histiocytes exhibited abundant pale cytoplasm, feathery cytoplasmic borders, and emperipolesis.

A few histiocytes had longitudinal nuclear grooves resembling Langerhans cells; however, these cells were positive for S-100 protein and negative for CD1a. The clinical presentation of the cutaneous variant of Rosai-Dorfman disease is generally nonspecific. We present this case because of the unusual clinical presentation mimicking a vasculitis.

Cutaneous rosai-dorfman disease is a distinct clinical entity.

Brenn T, Calonje E, Granter SR, Leonard N, Grayson W, Fletcher CD, McKee PH.

Am J Dermatopathol 2002 Oct;24(5):385-91 Abstract quote

Rosai-Dorfman disease (RDD) is a rare but distinctive clinicopathologic entity of unknown etiology affecting lymph nodes as well as extranodal sites. Although cutaneous involvement in RDD is common, purely cutaneous disease is rare and not well documented.

We report 22 patients with cutaneous and superficial subcutaneous RDD. The lesions presented as papules and nodules, often with discoloration (9/22) and frequent multifocality (13/22), without predilection for a specific site of the body. Age distribution was wide and ranged from 15 to 68 years, with a median of 43.5 years. Of the 17 patients for whom information on racial background was available, 7 were Asian, 8 were white, and 2 were black, with a marked female predominance (2:1). The lesions resolved in 6 of 13 patients for whom follow-up data were available, regardless of the treatment given. Lesions persisted or recurred in 7 patients.

Histologically, the lesions are invariably characterized by a proliferation of polygonal S100-positive histiocytes showing emperipolesis and a mixed inflammatory infiltrate. This study characterizes the histologic spectrum of cutaneous RDD in regard to variation in the numbers of typical S100-positive histiocytes and emperipolesis, variation in the quality and quantity of the inflammatory response, and the degree of stromal fibrosis, which resulted in a strikingly storiform growth pattern in six lesions and a lobulated pattern in two lesions.

Whereas the clinical as well as histologic appearance of the cutaneous and subcutaneous lesions in the purely extranodal forms of RDD is indistinguishable from that of systemic RDD, this study emphasizes that purely cutaneous RDD is a distinct clinical entity in regard to its epidemiology and remains localized to the skin even with long-term follow-up. Patients with purely cutaneous RDD are of an older age at onset of disease (median = 43.5 years), with a reversed male/female ratio. There are no significant systemic extracutaneous or serologic manifestations. Whereas systemic RDD is commonly seen in blacks and only rarely reported in Orientals, the majority of the patients in this series with purely cutaneous RDD are Asians and whites.


Otolaryngologic manifestations of Rosai-Dorfman Disease.

Ahsan SF, Madgy DN, Poulik J.

Department of Otolaryngology, Children's Hospital of Michigan, Wayne State University, 4941 Heather Drive, #105 Dearborn, MI 48126, USA.

Int J Pediatr Otorhinolaryngol 2001 Jul 2;59(3):221-7 Abstract quote

PURPOSE: To describe an unusual head and neck occurrence of Rosai-Dorfman Disease (RDD) and to review the otolaryngologic manifestations of this rare entity.

METHODS: A case presentation with review of the literature describing Rosai-Dorfman Disease and its head and neck involvement. Setting: A tertiary care, urban children's hospital.

RESULTS: This is the first description, to the best of our knowledge, of RDD [Sinus Histiocytosis with Massive Lymphadenopathy (SHML)] involving bilateral external auditory canals and middle ear in a 12 year old patient previously diagnosed with 'asthma' and hearing loss. This patient also had extensive involvement of the tracheobronchial tree. Representative clinical, radiographic and histological findings are presented. Its etiology, diagnosis and management are also reviewed.

CONCLUSION: This is the first reported case of middle ear and external auditory canal involvement of RDD in a patient with hearing loss and associated tracheobronchial lesions. RDD, although rare, may be considered in the differential diagnosis of unusual histiocytic lesions of the external auditory canal, especially with findings of similar or comparable lesions involving the respiratory tract. Confirmation is with identification of emperipolesis and appropriate immunohistochemical staining (S-100 positive, CD-68 positive and CD-1a negative). Intervention is recommended in cases where there is increased risk of mortality, as in severe obstruction of the tracheobronchial tree. Otherwise, since these lesions are self-limiting, the patients can be observed closely.


Rosai-Dorfman disease of the parotid gland: cytologic and histopathologic findings with immunohistochemical correlation.

Juskevicius R, Finley JL.

Department of Pathology, Brody School of Medicine, East Carolina University, Greenville, NC 27858-4354, USA

Arch Pathol Lab Med 2001 Oct;125(10):1348-50 Abstract quote

Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown origin and a distinct clinicopathologic entity also known as sinus histiocytosis with massive lymphadenopathy. The disease can involve extranodal tissues and rarely can present as salivary gland enlargement without significant lymphadenopathy. Involvement of the extranodal head and neck sites appears to be more common in patients with immunologic abnormalities. The disease was first described in 4 patients in 1969, and with later descriptions of more patients, the disease was established as a well-defined clinicopathologic entity. The characteristic pathologic feature of this disease is proliferation of distinctive histiocytic cells that demonstrate emperipolesis in the background of a mixed inflammatory infiltrate, consisting of moderately abundant plasma cells and lymphocytes. Fine-needle aspiration biopsy can be helpful in establishing the correct diagnosis, since surgical treatment is not necessary other than obtaining tissue for definitive diagnosis.

We describe cytologic, histopathologic, and immunohistochemical features of a case of Rosai-Dorfman disease that involved a major salivary gland without significant lymphadenopathy in a 48-year-old patient with systemic lupus erythematosus. We also briefly discuss possible causes and pathogenesis and review the literature.


Rosai-Dorfman disease of the larynx.

Aluffi P, Prestinari A, Ramponi A, Castri M, Pia F.

Department of Otorhinolaryngology, University of Piemonte Orientale, Novara, Italy

J Laryngol Otol 2000 Jul;114(7):565-7 Abstract quote

We present a case of an 81-year-old man with a history of worsening dysphonia of six months duration.

A year before a sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) was diagnosed on a submandibular lymph node biopsy. On presentation the patient showed a mass in the left subglottic area with a modest reduction in the airway space. The patient underwent an endoscopic CO2 laser excision of the mass, without post-operative complications.

Histopathological examination and electron microscope images confirmed the previous diagnosis of Rosai-Dorfman disease. The clinical and pathological features of this entity are discussed.


Relapsing bilateral uveitis and papilledema in sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease).

Pivetti-Pezzi P, Torce C, Colabelli-Gisoldi RA, Vitale A, Baccari A, Pacchiarotti A.

Institute of Ophthalmology, University La Sapienza, Roma, Italy.

Eur J Ophthalmol 1995 Jan-Mar;5(1):59-62 Abstract quote

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) is a non-hereditary histiocytic proliferative disorder affecting young people, with extranodal manifestations in 28-43% of cases. Eye involvement is infrequent. Lymphoproliferation in the soft tissues of the orbit and in the lids has been reported in 12% of cases but intraocular involvement is rare.

We describe the case of a 12-year-old boy affected by Rosai-Dorfman disease with bilateral relapsing uveitis and papilledema that appeared four years before the onset of lymphadenopathy.

Sinus histiocytosis with massive lymphadenopathy involving the orbit: reversal of compressive optic neuropathy after chemotherapy.

Goldberg S, Mahadevia P, Lipton M, Rosenbaum PS.

Department of Ophthalmology and Visual Sciences, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10467, USA.

J Neuroophthalmol 1998 Dec;18(4):270-5 Abstract quote

A 38-year-old woman from Antigua had compressive optic neuropathy of the right eye caused by orbital involvement with sinus histiocytosis.

There was also nasal sinus involvement and massive cervical lymphadenopathy resulting in radiographic compression of the airway and carotid sheath. Because of the compressive optic neuropathy and threat to the airway and carotid perfusion, the patient underwent a 6-month chemotherapeutic regimen of cyclophosphamide, vincristine, and prednisone. After chemotherapy, the visual dysfunction resolved in correlation with diminution of the orbital mass, and marked regression of the cervical lymphadenopathy.

This case demonstrates the potential efficacy of chemotherapy in the treatment of compressive optic neuropathy in cases of orbital sinus histiocytosis with massive lymphadenopathy.


Marginal corneal infiltrates: a possible new manifestation of sinus histiocytosis with massive lymphadenopathy.

Rumelt S, Cohen I, Rehany U.

Department of Ophthalmology, Western Galilee-Nahariya Medical Center, Nahariya, Israel

Cornea 2000 Nov;19(6):857-8 Abstract quote

PURPOSE: To describe unilateral deep marginal corneal infiltrates and chronic anterior uveitis in a young patient with sinus histiocytosis and massive lymphadenopathy.

METHODS: A 20-year-old man with a painless enlargement of his cervical lymph nodes was followed for five years after debulking of these nodes on the right side for right chronic anterior uveitis and deep marginal corneal infiltrates.

RESULTS: Histological sections of cervical lymph node confirmed the diagnosis of sinus histiocytosis with the typical emperipolesis. The uveitis partially responded to topical corticosteroid treatment but tended to recur upon its withdrawal. The marginal corneal infiltrates resolved gradually over a period of five years.

CONCLUSIONS: Marginal corneal infiltrates and uveitis may presumably be associated with sinus histiocytosis. Patients with sinus histiocytosis should also be screened for rare ocular involvement, such as uveitis and corneal infiltrates.


Rosai-Dorfman disease of the uterine cervix.

Murray J, Fox H.

Department of Pathology, South African Institute for Medical Research, Johannesburg.

Int J Gynecol Pathol 1991;10(2):209-13 Abstract quote

A case of Rosai-Dorfman disease of the uterine cervix is described.

The disease is characterized by a mixed chronic inflammatory cell infiltrate in which histiocytic cells predominate. A characteristic feature is the presence within many of the histiocytic cells of engulfed, but undamaged, lymphocytes. Rosai-Dorfman disease is of unknown etiology and pursues a benign course.

The disease can occur at a wide variety of extranodal sites, but this appears to be the first reported instance of female genital tract involvement.

Unusual bilateral renal histiocytosis. Extranodal variant of Rosai-Dorfman disease.

Afzal M, Baez-Giangreco A, al Jaser AN, Onuora VC.

Pathology Department, Central Laboratory Ministry of Health, Riyadh, Kingdom of Saudi Arabia.

Arch Pathol Lab Med 1992 Dec;116(12):1366-7 Abstract quote

A 37-year-old Bangladeshi presented with large bilateral masses involving the hilus of the kidneys. No lymphadenopathy was noted. Nephrectomy was performed. Histopathologically, it revealed a lymphohistiocytic and plasma cell inflammatory tumoral proliferation with characteristic lymphophagocytosis by the S100-positive-CD1-negative histiocytes.

Extranodal presentation of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) should be entertained in the differential diagnosis of bilateral masses involving the kidneys.


Rosai-Dorfman disease of the breast: a mimic of breast malignancy.

Ng SB, Tan LH, Tan PH.

Department of Pathology, Singapore General Hospital, Singapore. ere identified on electron microscopy.

Pathology 2000 Feb;32(1):10-5 Abstract quote

Rosai-Dorfman disease (RDD) or sinus histiocytosis with massive lymphadenopathy (SHML) is primarily a nodal-based, idiopathic, benign proliferative disorder of histiocytes with 43% of these cases also involving extranodal sites. The breast is an unusual site of occurrence of RDD.

We report two cases of this exceptional event. The first represents an intramammary nodal Rosai-Dorfman disease, while the second is an extranodal disease with sole involvement of the breast. In both, the possibility of malignancy was raised. Histological examination of the two breast lesions revealed sheets of characteristic large histiocytes displaying emperipolesis, a microscopic hallmark of this disease. Immunohistochemical and ultrastructural studies were also performed; the former showed cytoplasmic staining of histiocytes for S-100 protein, while histiocytes that engulfed lymphocytes and plasma cells were identified on electron microscopy.


The digestive system manifestations of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy): review of 11 cases.

Lauwers GY, Perez-Atayde A, Dorfman RF, Rosai J.

Department of Pathology, University of Florida School of Medicine, Gainesville 32610-0275, USA.

Hum Pathol 2000 Mar;31(3):380-5 Abstract quote

Rosai-Dorfman disease (RDD), originally described as sinus histiocytosis with massive lymphadenopathy, is a rare histiocytic proliferative disorder with a distinctive microscopic appearance. Formerly thought to be a process limited to lymph nodes, involvement by RDD has now been documented in many organ systems, notably bone, skin and soft tissue, central nervous system, eye and orbit, and upper respiratory tract. The digestive system, however, is affected only exceptionally, as reflected by the existence of only a handful of individual case reports.

In this article, we report 11 patients in which the disease involved intestinal tract, liver, or pancreas, and describe the most salient clinicopathologic features. The specific site of involvement within the digestive system was gastrointestinal tract in 5, liver in 5, and pancreas in 1. Most patients also had evidence of disease in other extranodal sites, as well as in 1 or more lymph node groups.


Rosai Dorfman disease of soft tissue.

Levine EA, Landry MM.

Department of Surgery, Louisiana State University School of Medicine at New Orleans.

Surgery 1994 May;115(5):650-2 Abstract quote

Rosai Dorfman disease (RDD), or sinus histiocytosis with massive lymphadenopathy, is a well-described phenomenon in lymph nodes and other organs. However, it has only recently been described as a distinct entity in soft tissue.

Here we present what we believe to be the first report of a case of multiply recurrent RDD occurring exclusively in the soft tissue. Recognition that RDD of soft tissues can be a pernicious locally recurrent lesion is important and suggests that an aggressive surgical approach to this lesion may be warranted.

Soft tissue Rosai Dorfman disease mimicking inflammatory pseudotumor: a diagnostic pitfall.

Veinot JP, Eidus L, Jabi M.

Department of Laboratory Medicine, Ottawa Civic Hospital, Ontario, Canada.

Pathology 1998 Feb;30(1):14-6 Abstract quote

Rosai Dorfman disease, or sinus histiocytosis with massive lymphadenopathy (SHML), may be a difficult diagnosis to make, especially in extranodal sites. With soft tissue involvement the characteristic diagnostic features of large histiocytic cells with emperipolesis may be overshadowed by a fibroinflammatory component. In these cases it is easy to confuse this lesion with reactive nodules and benign and malignant neoplasms.

We report a case in which soft tissue SHML was confused with an inflammatory pseudotumor. Only after review, when other extranodal sites became apparent, was the correct diagnosis made. Pitfalls in the diagnosis of soft tissue SHML are discussed.


General-Lymph Node

The characteristic histology is a greatly enlarged lymph node with dilatation of the sinuses

Within these expanded sinuses are numerous histiocytes exhibiting emperipolesis or engulfment of lymphocytes


Focal changes of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) associated with nodular lymphocyte predominant Hodgkin's disease.

Maia DM, Dorfman RF.

Department of Pathology, Stanford University Medical Center, CA 94305, USA.

Hum Pathol 1995 Dec;26(12):1378-82 Abstract quote

Sinus histiocytosis with massive lymphadenopathy (SHML/Rosai-Dorfman disease) has, on rare occasions been identified as an isolated phenomenon in lymph nodes affected by malignant lymphomas.

The Registry includes four cases of SHML in patients with non-Hodgkin's lymphomas and one with multiple myeloma. SHML has more recently been recorded as a focal finding in lymph nodes involved by Hodgkin's disease of the mixed cellularity type.

We report two patients presenting with lymphadenopathy caused by involvement by nodular lymphocyte predominant Hodgkin's disease with focal changes of SHML, an association not previously recorded in the literature.

Responsiveness of the histiocytic cells of SHML to B-cell derived cytokines is postulated as a mechanism for this phenomenon, an hypothesis previously raised in regard to the association of focal Langerhans cell histiocytosis with Hodgkin's disease and with non-Hodgkin's lymphomas.

Crystal Deposition in a Case of Cutaneous Rosai-Dorfman Disease.

Motta L, McMenamin ME, Thomas MA, Calonje E.

From the *Department of Dermatopathology, St. John's Institute of Dermatology, St. Thomas' Hospital, London, UK; daggerDepartment of Histopathology, St. James's Hospital, Dublin, Ireland; and double daggerAl Mafraq Hospital, Abu Dhabi, United Arab Emirates.
Am J Dermatopathol. 2005 Aug;27(4):339-342. Abstract quote  

Rosai-Dorfman Disease (RDD) is an idiopathic reactive proliferation of distinctive histiocytes that have abundant cytoplasm and commonly exhibit intracytoplasmic ingestion of inflammatory cells (emperipolesis). The histiocytes are immunopositive for S100 protein and are typically associated with an infiltrate of lymphocytes, plasma cells, and neutrophils. The classic clinical presentation is massive enlargement of (usually) cervical lymph nodes with a histologic appearance that mimics exaggerated sinus histiocytosis. RDD can also involve extra-nodal sites and skin involvement is common either as part of disseminated disease or as a result of primary disease.

We report an exceptional case of cutaneous RDD with crystal deposition in a young male presenting with skin nodules. Skin biopsy showed classic features of cutaneous RDD with the additional feature of conspicuous rhomboidal and needle-shaped crystals within the cytoplasm of many lesional plasma cells, histiocytes, and also in an extra-cellular location. The plasma cells were polyclonal by light chain immunostaining.

Crystal deposition has not been reported to date in RDD and is likely a result of the reactive plasma cell proliferation.


Special stains  

Hum Pathol 1989; 20:711-715

Histiocytic cells are strongly positive for S100

Immunophenotypic characterization of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease).

Eisen RN, Buckley PJ, Rosai J.

Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.

Semin Diagn Pathol 1990 Feb;7(1):74-82 Abstract quote

Histochemical and immunohistochemical studies have been reported in only a few cases of sinus histiocytosis with massive lymphadenopathy (SHML) to date. These indicate that SHML cells belong to the macrophage/histiocyte family, but their exact origin is still unknown.

We determined the antigenic phenotype of SHML cells in sections from 20 cases of routinely fixed, paraffin-embedded tissue and from two cases of fresh frozen tissue using a broad panel of antibodies to macrophage/histocyte, B-, and T-cell antigens. SHML cells expressed the following: (1) S-100 protein, (2) "pan-macrophage" antigens such as EBM11, HAM 56, and Leu-M3, (3) antigens functionally associated with phagocytosis (Fc receptor for IgG, complement receptor 3), and lysosomal activity (lysozyme, alpha 1-antichymotrypsin, and alpha 1-antitrypsyn), (4) antigens associated with early inflammation (Mac-387, 27E10), (5) antigens commonly found on monocytes, but not tissue macrophages (OKM5, Leu-M1), and (6) "activation" antigens (Ki-1 and receptors for transferrin and interleukin 2).

These data suggest that SHML cells are true functionally activated macrophages that may be recently derived from circulating monocytes.

Immunophenotypic characterization of the cell infiltrate in five cases of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease).

Paulli M, Rosso R, Kindl S, Boveri E, Marocolo D, Chioda C, Agostini C, Magrini U, Facchetti F.

Department of Pathology, IRCCS Policlinico S. Matteo, Pavia, Italy.

Hum Pathol 1992 Jun;23(6):647-54 Abstract quote

Little is known about the nature of the large intrasinusoidal cells exhibiting cytophagocytosis, which are the histologic hallmark of sinus histiocytosis with massive lymphadenopathy (SHML) (Rosai-Dorfman disease).

Using a broad panel of monoclonal and polyclonal antibodies, we analyzed the immunophenotype of the cell infiltrates in seven lymph node biopsy specimens from five cases of SHML. The SHML cells constantly expressed the S-100 protein, concanavalin agglutinin and peanut agglutinin lectins, and monocyte-macrophage-associated antigens CD 11c, CD 14, CD 33, CD 68, and LN 5. Labeling with other antimacrophage antibodies was extremely variable, with some (MAC 387, lysozyme) restricted to clusters of SHML cells and others (CD11b, CD 36, alpha-1-antichymotrypsin) staining only scattered cells. The CD 1a antigen was found on some cells in only one case, whereas HLA-DR and the HLA-DR-associated invariant chains were absent. The heterogeneity of SHML cell marker expression might be related to the local content of factors (eg, cytokines) capable of modulating the phenotype of monocytes and derived cells. All cases presented with huge amounts of medium-sized mononuclear cells accumulated in the sinuses and intersinusoidal tissue.

These cells expressed the S-100-/CD 11b+/CD 11c+/CD 14+/CD 16+/CD 33+/CD 36+/lysozyme+/MAC 387+/HLA-DR+ phenotype. These recently immigrated monocytes might represent the immediate precursors of SHML cells.


Sinus histiocytosis with massive lymphadenopathy and Langerhans cell histiocytosis express the cellular adhesion molecule CD31.

Slone SP, Fleming DR, Buchino JJ.

Department of Pathology and Laboratory Medicine, School of Medicine, University of Louisville, Louisville, KY 40292, USA.

Arch Pathol Lab Med 2003 Mar;127(3):341-4 Abstract quote

Context.-We investigated expression of the adhesion molecule CD31 in sinus histiocytosis with massive lymphadenopathy (SHML) and Langerhans cell histiocytosis (LCH) because (1) SHML and LCH cells express a variety of cellular adhesion molecules and (2) SHML has been characterized as a reactive histiocytic proliferation, and tissue macrophages (histiocytes) are known to express CD31.

Objective.-The purpose of this study was to determine whether SHML and LCH cells express CD31 and whether dual staining with CD31 and S100 facilitates diagnosis of these disease states.

Methods.-Formalin-fixed, paraffin-embedded archival tissues were immunohistochemically stained via the labeled streptavidin-biotin method using antibodies against CD31 and S100 protein after heat-induced epitope retrieval. Archival tissues included SHML (n = 2), LCH (n = 10), malignant melanoma (n = 5), sinus hyperplasia (n = 4), granulomas (n = 4), granular cell tumor (n = 6), and normal skin (n = 4). Results.-Normal Langerhans cells in the epidermis were CD31(-)/S100(+); neoplastic Langerhans cells in LCH were CD31(+)/S100(+). Histiocytes in granulomas and in sinus hyperplasia were CD31(+)/S100(-); abnormal histiocytes in SHML were CD31(+)/S100(+). S100(+) tumors (malignant melanoma and granular cell tumor) were CD31(-).

Conclusions.-The spectrum of cell types that express CD31 is expanded to include SHML and LCH. We speculate that up-regulation of CD31 in neoplastic Langerhans cells contributes to the migratory capability of LCH cells. CD31 may be a useful nonlysosomal marker of macrophages and their neoplastic counterparts (true histiocytic sarcomas). An immunohistochemical staining panel that includes CD31 and S100 facilitates the diagnosis of SHML and LCH.



Emperipolesis in a case of B-cell lymphoma: A rare phenomenon outside of Rosai-Dorfman disease.

Lopes LF, Bacchi MM, Coelho KI, Filho AA, Bacchi CE.
Ann Diagn Pathol. 2003 Oct;7(5):310-3. Abstract quote  

We describe a case of a diffuse large B-cell lymphoma with extensive emperipolesis phenomenon. Light microscopy revealed numerous CD68-positive/S-100-negative histiocytes containing viable neoplastic hematopoietic cells in their cytoplasm. Electron microscopy confirmed these findings. In this case, there was no evidence of Rosai-Dorfman disease either clinically or histologically.

This report emphasizes that emperipolesis is not restricted to Rosai-Dorfman disease and can be found in other conditions including non-Hodgkin lymphomas.


Sinus histiocytosis of pelvic lymph nodes after hip replacement. A histiocytic proliferation induced by cobalt-chromium and titanium.

Albores-Saavedra J, Vuitch F, Delgado R, Wiley E, Hagler H.

Department of Pathology, University of Texas Southwestern Medical Center, Texas, Dallas 75235-9072.

Am J Surg Pathol 1994 Jan;18(1):83-90 Abstract quote

Six men who had undergone hip replacements for degenerative joint disease or trauma subsequently had radical prostatectomies or cystoprostatectomies with bilateral pelvic lymph node dissections for adenocarcinoma of the prostate or transitional cell carcinoma of the urinary bladder.

The hip prostheses implanted in three patients were known to contain cobalt-chromium alloy and titanium. The pelvic lymph nodes ipsilateral to the hip prosthesis in five patients and the bilateral pelvic nodes in the only patient with bilateral hip prosthesis had dark brown or black cut surfaces. These lymph nodes did not contain carcinoma but showed florid sinus histiocytosis characterized by large polygonal histiocytes filling and expanding sinuses and interfollicular regions. The foamy histiocytes contained cobalt-chromium and titanium microparticles by light microscopy, ultrastructure, and energy-dispersive x-ray microanalysis. The lymph nodes uninvolved by the histiocytic reaction lacked the heavy metal microparticles. Four cases were found to have a small number of polyethylene particles, which might have contributed to the histiocytic response. By immunohistochemistry, the foamy cells displayed immunoreactivity for lysozyme, alpha-1-antitrypsin, alpha-1-antichymotrypsin, and cathepsin D, providing additional support for their histiocytic derivation.

To our knowledge, this is the first time that microparticles of cobalt-chromium and titanium that migrate from hip prostheses to pelvic lymph nodes have been shown to elicit a distinctive type of florid sinus histiocytosis. Pathologists should be aware of this characteristic foreign-body tissue response to avoid confusion with other types of sinus histiocytosis or with metastatic carcinoma.

Rosai-Dorfman disease mimicking parasagittal meningioma: case presentation and review of literature.

Kattner KA, Stroink AR, Roth TC, Lee JM.

Division of Neurosurgery, Central Illinois Neuroscience Foundation, Bloomington, IN 61701, USA.

Surg Neurol 2000 May;53(5):452-7 Abstract quote

BACKGROUND: Sinus histiocytosis with massive lymphadenopathy was originally described by Rosai and Dorfman in 1969. It usually presents with bilateral painless cervical lymphadenopathy. In extremely rare circumstances, the CNS can be affected. Only 21 prior cases of intracranial involvement have been reported.

CASE REPORT: A 33-year-old white male presented with a 2-week history of progressive cephalgia. The patient underwent MRI testing that revealed an enhancing mass in the right parasagittal region with associated edema. Preoperative diagnosis was right parasagittal meningioma. The patient underwent craniotomy with complete resection of the mass. Histopathology was compatible with Rosai-Dorfman disease (RDD).

CONCLUSION: Rosai-Dorfman disease is rarely found intracranially; however, its ability to mimic meningioma as well as other pathologies underlines its importance. With so few reported cases of intracranial involvement, more experience will be necessary before this clinical presentation and prognosis can be clearly outlined.



Sinus histiocytosis with massive lymphadenopathy. An analysis of 14 deaths occurring in a patient registry.

Foucar E, Rosai J, Dorfman RF.

Cancer 1984 Nov 1;54(9):1834-40 Abstract quote

Sinus histiocytosis with massive lymphadenopathy (SHML) is generally regarded as a benign disorder in spite of its propensity to form large masses and to disseminate to both nodal and extranodal sites. Although in most patients the extent of SHML does not appear to determine disease outcome, recent reports have documented that infiltrates of SHML can cause death.

To gain perspective on the role of SHML in patient deaths in this population, the authors analyzed the 14 known fatalities in an SHML registry comprising 215 patients.

The average age at death was 33 years. Autopsy was performed on eight patients. SHML infiltrates were clearly the cause of death in only two patients (previously reported). In another four cases persistent SHML was prominent at death. The other deaths were the result of complications of defined immunologic abnormalities (five), or of unusual infections (three). The authors have not seen an example of cytologic malignant transformation of SHML.

Major indication is for life or function-threatening obstruction

Semin Diagn Pathol 1990; 7:83-86

Most effective regimens in a review of many cases include a vinca alkaloid combined with an alkylating agent and corticosteroid

Overall the response rates are inferior to those seen in other hematopoietic diseases such as malignant lymphoma or Histiocytosis X

Radiation therapy

Semin Diagn Pathol 1990; 7:83-86

Review of 34 patients found 10/34 with complete or partial response
6/18 with dose specified RT had favorable responses

Usually utilized for threatened function such as spinal cord compression or respiratory embarrassment

Overall, responses were inferior to those expected with malignant hematopoietic neoplasms

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Cancer 1972; 30:1174-1188
Arch Pathol Lab Med 1985; 109:867-870
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Commonly Used Terms

Emperipolesis-Phagocytosis of lymphocytes within histiocytes.

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