Primary pancreatic sinus histiocytosis with massive lymphadenopathy (rosai-dorfman disease): an unusual extranodal manifestation clinically simulating malignancy.
Abstract: * Sinus histiocytosis with massive lymphadenopathy (SHML), also called Rosai-Dorfman disease, is a rare entity. Its etiology and pathogenesis are still essentially unclear. The histologic hallmark of this disease is proliferation of distinctive histiocytes within lymph node sinuses and in extranodal sites. Approximately 23% of patients with SHML, documented in the SHML Registry, presented with disease primarily in extranodal sites, and very few cases of SHML (<1%) involving the gastrointestinal system have been described in the literature. We report an unusual case of primary pancreatic SHML with infiltration of the process into peripancreatic, perinephric, and perisplenic adipose tissue, simulating malignancy.

(Arch Pathol Lab Med. 2010;134:276-278)
Article Type: Disease/Disorder overview
Subject: Lymphadenopathy (Development and progression)
Lymphadenopathy (Diagnosis)
Histiocytosis (Development and progression)
Histiocytosis (Diagnosis)
Authors: Podberezin, Mark
Angeles, Ronald
Guzman, Grace
Peace, David
Gaitonde, Sujata
Pub Date: 02/01/2010
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 College of American Pathologists ISSN: 1543-2165
Issue: Date: Feb, 2010 Source Volume: 134 Source Issue: 2
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230245849
Full Text: Sinus histiocytosis with massive lymphadenopathy was described by Rosai and Dorfman in 19691 and, therefore, received the eponym Rosai-Dorfman disease (RDD). The disease occurs most often in children and young adults. It is a rare disorder of unknown origin (with 423 cases described in the RDD registry), which is characterized by a nonneoplastic proliferation of distinctive histiocytic cells within lymph node sinuses and in extranodal sites.2,3 Themorecommonorgans affected by primary extranodal RDD are skin, soft tissue, nasal cavity and paranasal sinuses, eye and orbit, bone, central nervous system, and salivary glands. The digestive system is one of the least common sites of involvement by RDD, (4) and to our knowledge, only 2 pathologically confirmed cases of primary pancreatic RDD have been reported to date. (5,6) We describe a case of primary pancreatic RDD infiltrating into the peripancreatic, perinephric, and perisplenic adipose tissue, simulating malignancy.


A 35-year-old, Hispanic woman presented with abdominal pain in December 2003. Initially, her symptoms improved with some diet modification, and specific treatment was not initiated. Computed-tomography imaging, performed 6 months later because of persistent discomfort, revealed a mass in the tail of the pancreas. Fine-needle aspiration biopsy of this mass showed features suggestive of RDD. The mass, which measured 10.2 X 5.1 X 2.5 cm, was eventually partially excised in July 2005. Before resection, a repeat computed-tomography image demonstrated a new mass involving the thoracic spine at T11 to T12. Histologic sections showed fibrotic tissue with focal edema, scattered blood vessels, plasma cells, lymphocytes, and numerous histiocytes, which were positive for S100. Rare histiocytes with emperipolesis were noted. In March 2006, she presented with left upper-quadrant pain, vomiting, and lower back pain. Positron emission tomography scans revealed a recurrent pancreatic tail mass extending into the left subdiaphragmatic region and left pararenal space (Figure 1) and 2 additional masses in the left paraspinal region at T10 to T12 (1.6 X 1.1 cm in size) and the parasacral space (2.5 cm in greatest dimension). Multiple medical treatment approaches were attempted to alleviate symptoms, including high-dose steroids, thalidomide, 2-chlorodeoxyadenosine, and imatinib mesylate but were all essentially ineffective. In January 2008, the patient underwent a splenectomy, partial colectomy, nephrectomy, and partial pancreatectomy.


The surgical specimen demonstrated a tan, firm, and poorly circumscribed multinodular mass, occupying the distal 2.5-cm part of pancreatic tail and extending into the peripancreatic adipose tissue and into the splenic hilum (Figure 2). There were white, fibrotic streaks involving the peripancreatic, perinephric, and perisplenic adipose tissues. The kidney, spleen, and bowel parenchyma were uninvolved. These organs were removed because of the fibrosis that made the surgery difficult. The microscopic examination revealed a fibrotic mass with a predominantly lymphohistiocytic infiltrate surrounding the native pancreatic acinar parenchyma (Figure 3) and extending into the surrounding adipose tissue. Few plasma cells and rare eosinophils were present. Among the mature collagen bundles were large histiocytes with abundant vacuolated cytoplasm and small, round central nuclei with distinct nucleoli and small, mature lymphocytes. Rare histiocytes demonstrated intracytoplasmic lymphocytes, also known as emperipolesis or lymphophagocytosis. The histiocytes were negative for CD1a and strongly expressed CD68 and S100 (Figures 4 and 5), which was consistent with the diagnosis of RDD. Three periaortic lymph nodes, submitted separately from the main specimen, were not involved by RDD.


Primary pancreatic RDD is a very rare entity. Only 2 cases have been previously reported in the literature. (5,6) Gregor and Ninnin (7) described a case of presumed pancreatic involvement by RDD, according to radiological studies, but there was no biopsy confirmation. Another published case reported pancreatic involvement as a part of widespread involvement by RDD. (8) The main clinical differential diagnosis is primary pancreatic malignancy, which also presents as a mass lesion of the pancreas and requires more radical therapy. Extranodal RDD readily simulates malignancy because it presents as a mass lesion9 and can be both infiltrative and multifocal, as seen in this case. Other differential diagnoses would include immunoglobulin G4-mediated autoimmune pancreatitis, Langerhans cell histiocytosis, and other histiocytic disorders. Establishing the accurate diagnosis is extremely important to prevent unnecessary therapy. Clinical and laboratory findings may aid in the diagnosis because they include findings associated with autoimmunity (ie, polyarthralgia, rheumatoid arthritis, glomerulonephritis, asthma, diabetes mellitus, polyclonal hypergammaglobulinemia, rheumatoid factor, antinuclear antibodies, and reversal of the CD4:CD8 ratio). (10,11) Our patient did not present with these symptoms. The unfavorable clinical outcome in patients with associated immune dysfunction has led to the consideration that sinus histiocytosis with massive lymphadenopathy results from an exuberant response of the hematopoietic system to an, as yet undetermined, immunologic trigger. Recently, cases of sinus histiocytosis with massive lymphadenopathy associated with autoimmune lymphoproliferative syndrome have been described. (12) However, histologic diagnosis on fine-needle aspiration and core needle biopsies is most important in establishing the diagnosis. Histiocytes exhibiting enlarged vesicular nuclei with well-defined nuclear membrane, single prominent nucleolus, and abundant eosinophilic or foamy cytoplasm in which intact lymphocytes may be found in variable numbers are the hallmark of RDD. The latter phenomenon is called emperipolesis or lymphophagocytosis. Although characteristic, many other cells can exhibit emperipolesis, such as megakaryocytes, epithelial cells, and mesenchymal cells. In this respect, careful morphologic and immunophenotypic assessment is necessary to confirm the histiocytes of RDD. It is important to mention that no one immunohistochemical stain is specific for the lesional cells of RDD. Histiocytes in this disorder express panmacrophage antigens (CD68, CD56, CD14, CD15). Only in this entity do CD68+ histiocytes coexpress S100. They also express antigens associated with phagocytosis (CD64 or immunoglobulin G Fc receptors), lysosomal activity (lysozyme, [alpha]-antitrypsin), and immune activation (transferring receptor and interleukin-2 receptor). (3) Histiocytes in RDD also express CD163, which is the hemoglobin-scavenger receptor. (13,14) Even though Langerhans cells are positive for CD1a, most RDD histiocytes are negative for CD1a (reason unknown) as well as for the dendritic cell markers (CD21, CD23, CD35). (3)


The characteristic emperipolesis described in nodal RDD is not easily identified in extranodal sites, making the diagnosis a further challenge. Judicial use of immunohistochemistry, therefore, cannot be overemphasized.

Several studies showing usefulness of fine-needle aspiration in establishing the diagnosis and the defining cytologic features of RDD15 have been published. The cytologic diagnosis rests on the identification of RDD histiocytes with emperipolesis. Limitations include sampling errors as well as technically insufficient material because of abundant fibrosis. Triaging adequate material for the cell block is necessary during image-guided biopsies for confirmation of the characteristic immunophenotype.

There is no established treatment for RDD. In most cases, it resolves spontaneously. When organ function is compromised or in life-threatening situations, different therapy options have been tried, including steroids, alkylating agents, and interferon [alpha], with variable success rates. Because of the rarity of the entity, there have not been, to our knowledge, any collaborative clinical trials. Poor prognostic variables include associated immunologic abnormalities, younger age, and extranodal involvement (kidney and liver). (16)


In summary, we present a case of primary pancreatic RDD with lesional histiocytes displaying emperipolesis as well as CD68+ and S100+ immunophenotype. This is the third report of such a presentation, according to our review. There is no consensus regarding treatment for such cases, although resection of the mass was performed in our case. After surgery, treatment with steroids was initiated, and since then, our patient feels better, without the low back pain. The left paraspinal tissue mass at T11 to T12 remains the same size and is asymptomatic. However, according to magnetic resonance imaging, the persisting masses in the presacral, left perirectal, and left common iliac areas have been increasing in size. Our patient has refused surgical excision of the other masses.


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Accepted for publication April 10, 2009.

From the Departments of Pathology (Drs Podberezin, Guzman, Angeles, and Gaitonde) and Hematology/Oncology (Dr Peace), University of Illinois, Chicago.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Sujata Gaitonde, MD, Department of Pathology (MC 847), College of Medicine, University of Illinois, 840 S Wood St, Rm 110 CSN, Chicago, IL 60612 (e-mail:
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