History: A 69-year-old African American female had chronic epigastric and back pain post hiatal hernia repair.

Radiology: Abdominal computed tomography scan was performed and revealed a 2.5 cm, solid pancreatic tail mass with associated pancreatic duct dilation. Radiologically this was suspicious for either pancreatic ductal adenocarcinoma or a neuroendocrine tumor.

FNA: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was performed after which the patient elected to have a distal pancreatectomy and splenectomy. The following images (Figures 1 – 6) are from the EUS-FNA and subsequent pancreatectomy specimens.

Figure 1. Smear from fine needle aspiration of pancreatic mass (Papanicolaou stain, 400x magnification).
Figure 1. Smear from fine needle aspiration of pancreatic mass (Papanicolaou stain, 400x magnification).


Figure 2. Bi-valved distal pancreatectomy specimen.
Figure 2. Bi-valved distal pancreatectomy specimen.


Figure 3. Low power image of pancreatic mass (H&E stain, 100x magnification).
Figure 3. Low power image of pancreatic mass (H&E stain, 100x magnification).


Figure 4. Intermediate power image of pancreatic mass (H&E stain, 200x magnification).
Figure 4. Intermediate power image of pancreatic mass (H&E stain, 200x magnification).


Figure 5. High power image of pancreatic mass (H&E stain, 400x magnification).


Figure 6. High power image of pancreatic mass (H&E (left) and Elastin stain (right), 400x magnification).
Figure 6. High power image of pancreatic mass (H&E (left) and Elastin stain (right), 400x magnification).


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Based on the microscopic findings which of the following conditions does this patient most likely have?

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Answer e. Sinus histiocytosis with massive lymphadenopathy


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Images

The smear (Figure 1) shows a large histiocyte with abundant granular cytoplasm, large eccentric nucleus with prominent nucleoli and emperipolesis of neutrophils, lymphocytes, and debris. On cell block these cells were positive for S100, CD68 and CD163 (not shown), and negative for CD1a, IgG4, AFB and GMS. The cytomorphology and immunoprofile were compatible with sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Disease [RDD]). After diagnosis the patient refused steroid and radiation therapy and opted for distal pancreatectomy which confirmed the diagnosis. Gross examination revealed a 2.3 cm firm circumscribed and lobulated yellow mass (Figure 2). Histologic sections showed storiform pattern fibrosis and a lymphoplasmacytic infiltrate (Figure 3). In areas there were sheets of plump histiocytes with eccentric nuclei, prominent nucleoli and abundant pale pink granular cytoplasm containing intracytoplasmic red blood cells and chronic inflammatory cells (emperipolesis) (Figure 4 -5). The latter were strongly positive for S100 and CD163. Focal obliterative phlebitis was also noted within the mass (Figure 6) and 2 of 14 peri-pancreatic lymph nodes were also involved by RDD.

Discussion

Sinus histiocytosis with massive lymphadenopathy or Rosai-Dorfman disease (RDD) is a rare benign histiocytic disorder characterized by proliferating S100-positive histiocytes. It was first described by Rosai in 1972 and is diagnosed by identification of proliferation of distinctive histiocytes on histopathologic review.1 Although originally described in lymph nodes, it can also involve extra-nodal sites including skin, lung, breast and other organs. GI involvement however is rare and pancreatic involvement is even less common, with fewer than 10 reported cases in the literature.2-6  RDD in the pancreas may present as a distinct mass and on imaging may be mistaken for ductal adenocarcinoma. Its’ morphology however is distinctive and the identification of the hallmark atypical histiocytes with emperipolesis of inflammatory cells should prompt performance of the appropriate discerning immunostains (S100 and histiocyte markers). The atypical histiocytes are characterized by large nuclei with pale or vesicular chromatin and nucleolar prominence, features not otherwise seen in typical histiocytes. Most cases of pancreatic RDD described in the literature were diagnosed on resection and there is only one report of a case that was diagnosed on fine needle aspiration, a procedure with significantly lower morbidity and mortality than pancreatectomy which is not indicated for the treatment of RDD.6 The case presented herein was also diagnosed on fine needle aspiration. However, because of the patient’s wishes a distal pancreatectomy was performed.

Based on morphology and location the main differentials include other fibro-inflammatory conditions particularly IgG4 related disease (autoimmune pancreatitis [AIP]). Recent studies have demonstrated overlapping features between RDD and IgG4 related disease, which may complicate pathologic diagnosis and distinction.7-10 These features include dense IgG4-positive lymphoplasmacytic infiltrates, increased fibrosis, including storiform fibrosis, and/or the presence of obliterative phlebitis/vasculitis. Marked fibrosis is a known manifestation of extra-nodal RDD that sometimes results in such significant histiocyte distortion that it may obscure their presence as well as the entity-defining emperipolesis. Although this patient showed major criteria for type 1 AIP the IgG4 immunostain showed no increase in IgG4-positive plasma cells nor were there ductal granulocytic epithelial lesions characteristic of type 2 AIP. Her serum IgG4 level was also not elevated. Chronic pancreatitis particularly that secondary to alcohol is also characterized by a chronic fibro-inflammatory process that results in loss of acini and ductal cells. However it does not show the proliferating atypical histiocytes seen in RDD.

Other differentials include granulomatous pancreatitis secondary to infection or sarcoidosis. The proliferating sheets of plump histiocytes that are seen in RDD may mimic necrotizing/non-necrotizing infection-related granulomas. However negative stains for acid-fast bacilli and fungi and as well as histiocyte positivity for S100 should allow accurate distinction between these two differentials. Additionally, conventional histiocytes of granulomatous disease are much smaller than those of RDD and have small oval or bean-shaped nuclei with small nucleoli, and are not of the markedly atypical type seen in RDD. Granular cell tumor (GCT), a rare benign neoplasm of Schwann cells, may occasionally involve the pancreas.11 Cytomorphologically GCT may show strong resemblance to the proliferating histiocytes in RDD. Additionally, both are positive for S100, which further compounds distinction. The identification of emperipolesis and the positive staining of the granular cells with histiocyte markers should facilitate the diagnosis of RDD and distinction from GCT.

When evaluating a mass-forming lesion in the pancreas, even in the presence of major histologic criteria of IgG4-related disease (AIP) and IgG4 positive plasma cells, RDD should be considered in the differential diagnosis and excluded with the appropriate stains.

References

  1. Rosai J, Dorfman RF: Sinus histiocytosis with massive lymphadenopathy: A pseudolymphomatous benign disorder. Analysis of 34 cases. 1972;30:1174-1188.
  2. Esquivel J, Krishnan J, Jundi M, Sugarbaker PH. Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) of the pancreas: first case report. Hepatogastroenterology. 1999;46:1202-1205.
  3. Lauwers GY, Perez-Atayde A, Dorfman RF, Rosai J. The digestive system manifestations of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy): review of 11 cases. Hum Pathol. 2000;31:380-385.
  4. Zivin SP, Atieh M, Mosier M, Paner GP, Aranha GV. Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) of the pancreas: second case report. J Gastrointest Surg. 2009;13:806-809.
  5. Romero Arenas MA, Singhi AD, Hruban RH, Cameron AM. Rosai-dorfman disease (sinus histiocytosis with massive lymphadenopathy) of the pancreas: third reported occurrence. J Gastrointest Cancer. 2012;43:626-629.
  6. Smith DJ, Sekhar A, Memis B, AdsayVN, Alese OB. Rosai-Dorfman Disease Menifesting as a Pancretaic Head Mass Diagnosed Nonoperatively. J Oncol Pract. 2017 Jan;13(1):61-62.
  7. Liu L, Perry AM, Cao W, et al. Relationship between Rosai-Dorfman disease and IgG4-related disease: study of 32 cases. Am J Clin Pathol. 2013;140:395-402.
  8. Zhang X, Hyjek E, Vardiman J. A subset of Rosai-Dorfman disease exhibits features of IgG4-related disease. Am J Clin Pathol. 2013;139:622-632.
  9. Kuo TT, Chen TC, Lee LY, Lu PH. IgG4-positive plasma cells in cutaneous Rosai-Dorfman disease: an additional immunohistochemical feature and possible relationship to IgG4-related sclerosing disease. J Cutan Pathol. 2009;36:1069-1073.
  10. Liu M, Li X, Li Y, et al. Rosai-Dorfman disease with features of IgG4-related disease in the breast: Cases report and literature review. Asian Pac J Allergy Immunol. 2018 Mar;36(1):51-57.
  11. Kanno A, Satoh K, Hirota M, Hamada S, Umino J, et al. Granular cell tumor of the pancreas: A case report and review of literature. World J Gastrointest Oncol. 2010 Feb 15; 2(2): 121–124.


Case contributed by:

Michelle D Reid, MD, MS

Professor Department of Pathology

Emory University Hospital

1364 Clifton Rd NE Room G179B

Atlanta GA 30322

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