BRIEF REPORTS

Rectal Extranodal Rosai–Dorfman Disease Diagnosed by EUS-FNA: A Case Report and Review of the Literature Ioannis Ioannidis, M.D.,1* Catherine Manolakis, M.D.,2 Javier A. Laurini, M.D.,1 Kelly P. Roveda, M.D.,1 Silvio de Melo Jr., M.D.,2 Brenda Avery, C.T. (ASCP),1 and Carole W. Boudreaux, M.D.1

Rosai–Dorfman disease (RDD), also known as “sinus histiocytosis with massive lymphadenopathy,” only rarely involves the gastrointestinal (GI) tract. Therefore, this unusual site of presentation can be challenging for the pathologist. We present a case of RDD manifesting as a rectal submucosal mass associated with rectal bleeding in a 54 year old woman. The diagnosis was made on cytologic preparations obtained through endoscopic ultrasound guided fine needle aspiration (EUS-FNA) and subsequently confirmed by biopsy. To our knowledge, this is the first time extranodal RDD of the GI tract has been diagnosed by EUS-FNA. A review of previously published cases of GI RDD is presented to increase awareness of this exceptional presentation. Diagn. Cytopathol. 2015;43:40–44. VC 2014 Wiley Periodicals, Inc. Key Words: Rosai–Dorfman disease; EUS-FNA; gastrointestinal tract

Rosai–Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare, usually self-limited disorder of unknown etiology characterized by an exuberant proliferation of large histiocytes. It was first described in 1969 by Rosai and Dorfman, and it typically presents in children or young adults with massive painless cervical lymphadenopathy, lowgrade fever, and weight loss.1,2 Histologically, the

1 Department of Pathology, University of South Alabama Medical Center, Mobile, Alabama 2 Division of Gastroenterology, University of South Alabama Medical Center, Mobile, Alabama *Correspondence to: I. Ioannidis, M.D., Department of Pathology, University of South Alabama Medical Center, 2451 Fillingim St., Mobile, AL 36617, USA. E-mail: [email protected] The authors declare no competing financial interests. Received 12 August 2013; Revised 4 December 2013; Accepted 9 January 2014 DOI: 10.1002/dc.23112 Published online 19 February 2014 in Wiley Online Library (wileyonlinelibrary.com).

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affected lymph nodes have sinuses markedly distended by numerous large histiocytes with abundant eosinophilic cytoplasm and vesicular nuclei, some of them showing binucleation or multinucleation. Many of these histiocytes show emperipolesis, defined as the presence of intracytoplasmic intact lymphocytes and/or plasma cells.1–4 Characteristically, the lesional histiocytes are positive for CD68 and S100 and negative for CD1a.5 Although the disease has a predilection for cervical lymph nodes in young children, examples of extranodal presentation involving all age groups have been reported.2–4 Moreover, extranodal involvement occurs in up to 40% of patients, and the sites most commonly affected are the skin and soft tissues, upper and lower respiratory tract, bones, genitourinary system, and the oral cavity.6 Involvement of the gastrointestinal (GI) system is extremely rare, with only 19 cases reported so far, all of which were diagnosed by endoscopic biopsy and/or surgical resection.6–16 Here we report a case of extranodal RDD in an adult patient with a submucosal rectal mass found at colonoscopy. The diagnosis was made in cytologic preparations obtained through endoscopic ultrasound guided fine needle aspiration (EUS-FNA) and subsequently confirmed by biopsy. To the best of our knowledge, our case represents the first example of extranodal RDD of the GI tract diagnosed by EUS-FNA

Case Report A 54-year-old African American female presented to the gastroenterology clinic with a history of rectal bleeding and intermittent abdominal pain for the past month. There was no history of fever, loss of appetite, or weight loss. Clinical examination revealed no hepatosplenomegaly or generalized lymphadenopathy. Digital rectal examination C 2014 WILEY PERIODICALS, INC. V

Diagnostic Cytopathology DOI 10.1002/dc

EXTRANODAL RDD BY EUS-FNA

Fig. 1. (a) Aggregates of histiocytes and other inflammatory cells transversed by branching capillaries (Pap stain, 4003). (b,c) Histiocytes engulfing inflammatory cells (Pap stain and Quick-Dip stain, 4003, respectively). (d) H&E sections confirm the presence of histiocytic aggregates encorporating inflammatory cells (4003).

was normal. Laboratory investigations revealed no anemia. Urine analysis was unremarkable. At the time of colonoscopy, a submucosal mass measuring approximately 1.5 3 0.5 cm was noted in the rectum. Multiple cold forceps biopsies revealed fragments of unremarkable large bowel mucosa with a small lymphoid aggregate in the lamina propria. However, no submucosal tissue was included in the biopsy specimens. Due to the suspicious nature of the lesion, further endoscopic evaluation was performed. At the time of the EUS procedure, the submucosal mass originally seen in the colonoscopy was grossly identified. By ultrasound, the hypoechoic lesion measured 1.1 3 1.0 cm, was confined to the submucosa and abutted the muscularis propria. This lesion was targeted for EUS-FNA. Additionally, two adjacent non-grossly visible submucosal lesions were noted by ultrasound examination measuring 0.7 3 0.3 cm and 0.8 3 0.5 cm that showed similar echographic characteristics. Although a 1.0 3 0.6 cm perirectal lymph node was also identified, neither FNA nor histologic examination of this lesion was attempted as the needle path would cross the submucosal nodule to access the lymph node, raising concern for sample contamination.

The cytologic smears stained with Quick-Dip (Mercedes Medical, Sarasota, FL) and Papanicolaou stains (Figs. 1a–c), revealed numerous large, mono- and multinucleated histiocytes with abundant pale eosinophilic cytoplasm and vesicular nuclei. Many of the histiocytes contained intracytoplasmic intact lymphocytes, plasma cells, or neutrophils, a phenomenon referred to as emperipolesis or lymphophagocytosis. Occasional aggregates of large histiocytes were transversed by branching capillaries. Very few histiocytes showed mild atypical features including nuclear enlargement, irregular nuclear contours, and nucleoli, but their rarity and the overall cytologic features made the diagnosis of a malignant process very unlikely. At the time of the procedure, the above morphologic findings were highly suggestive of extranodal RDD. However, in the presence of a histiocytic reaction, a portion of the sample was submitted for mycobacterial and fungal cultures, which were later reported as negative. The H&E sections of the biopsy specimen (Fig. 1d) confirmed the presence of sheets of enlarged histiocytes with abundant, pale eosinophilic cytoplasm and centrally located, large nuclei with occasional prominent nucleoli Diagnostic Cytopathology, Vol. 43, No 1

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IOANNIDIS ET AL. Table I. Reported cases of RDD involving the GI tract. Case

Ref.

GI site

Age/sex

Presentation

Lymph node enlargement

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

* 8 11 9 12 27 6 8 26 10 28 8 8 8 13

Rectum Rectum Rectum Colon Colon Colon Colon Colon Colon Colon Ileocecal Appendix Appendix Jejunum Liver

54 F 56 F 60 F 50 F 51F 79 M 62 F 53 F 49 F 24 F 55 F 4M 7F 13 M 2.5 M

Hematochezia Colonoscopy Hematochezia Hematochezia Hematochezia Abdominal pain Colonoscopy Colonic mass Hematochezia Vomiting Ileocecal mass RLQ mass NA Autopsy Liver nodule

Perirectal None NA Pericolonic Mediastinal None None Cervical, intraabdominal Mesenteric NA NA Cervical, mesenteric Cervical, inguinal, mediastinal Cervical Supraclavicular, mesenteric

16 17

8 8

Liver Liver

28 F 0.7 F

Liver scan Autopsy

Cervical Cervical, mediastinal, inguinal

18 19 20

14 15 8

Liver Liver Pancreas

21 M 7F 48 F

Hepatomegaly Hepatomegaly Pancreatic mass

Cervical, hilar, axillary, inguinal Cervical, axillary, submandibular Intraabdominal

Additional sites None None Abdominal wall None None Multiple sites None Peritoneal cavity None Pelvic organs None None Eye Bone Bone, eye, thymus, heart, kidney, CNS CNS, breast Bone, orbit, trachea, skin, spleen, heart None Skin, peritoneal cavity NA

Ref: Reference, * current case, NA: not available.

admixed with numerous plasma cells located around branching vessels. Immunoperoxidase staining using antibodies against CD1a (Dako, Carpinteria, CA), CD68 (DAKO, Carpinteria, CA), and S100 protein (Dako, Carpinteria, CA) revealed strong positivity in the large cells for S100 protein and CD68, confirming their histiocytic differentiation. Immunoperoxidase staining for CD1a was negative. The morphologic features in conjunction with the immunohistochemical results supported the diagnosis of extranodal RDD. Further evaluation of the patient included a CT of the chest, abdomen, and pelvis, which failed to demonstrate significant lymphadenopathy. The patient has been scheduled to follow-up with the hematology–oncology clinic.

Discussion Although originally described as a nodal-based disorder, it has become clear that RDD can present in several extranodal locations, mainly the skin, soft tissues, upper respiratory tract, and oral cavity.8 However, GI tract involvement is particularly uncommon. A review of the literature revealed only 19 previously reported cases of RDD involving the GI tract.6,8–16 The detailed information of these cases, as well as the current case, is summarized in Table I. Briefly, the age of the patients ranged from 0.7 to 79 years with a mean of 36 years. The male to female ratio was 1:3. Regarding the site of disease, seven cases involved the colon, two cases presented in the appendix, one case involved the small bowel and another one, the ileocecal valve. Outside the gut, five cases involved the liver and one presented as a pancreatic 42

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mass. Of note, liver involvement was usually seen in the setting of widespread disease, unlike cases arising in the gut. Only three cases, including the current one, involved the rectum. For rectal cases, hematochezia was the presenting sign in two cases while the remaining case came to clinical attention as incidental submucosal masses discovered at the time of routine colonoscopy. The rectal lesions affected patients older than 50 years and almost all patients had a favorable outcome.6,8 In the current case, there was echographic evidence of perirectal lymphadenopathy, but no evidence of systemic lymphadenopathy. As is sometimes the case for other submucosal lesions, mucosal biopsies obtained at the time of the initial colonoscopic evaluation were non-diagnostic in our case. Endoscopic ultrasound examination plays an important role in the work up of submucosal lesions in the large bowel.17 In the current case, endoscopic ultrasound revealed a well-demarcated hypoechoic submucosal area that appeared to contact the muscularis propria. Additionally, small satellite lesions not appreciated by visual examination were identified echographically. The differential diagnosis for well delimited hypoechoic submucosal lesions in the rectum includes GI stromal tumors, leiomyomas, neuroendocrine neoplasms, granular cell tumor, pancreatic rests, or metastatic deposits.17 The present case adds extranodal RDD to the differential diagnostic list. Our case also highlights the role of FNA in the diagnosis of RDD. The cytologic features of nodal and extranodal RDD have been previously described.4,18 Fine needle

Diagnostic Cytopathology DOI 10.1002/dc

EXTRANODAL RDD BY EUS-FNA

aspirates from affected areas usually reveal numerous large histiocytes with the presence of intracytoplasmic intact lymphocytes, plasma cells, neutrophils, or red blood cells. In the presence of the classic feature of emperipolesis or lymphophagocytosis, a diagnosis of RDD can reliably be made and as such, biopsy may be avoided.4,6,9 Furthermore, immunoperoxidase stains can be performed in cell blocks obtained at the time of the procedure to support the diagnostic interpretation. The lesional histiocytes are characteristically positive for S100 protein, a1antitrypsin, periodic acid-Schiff (PAS), CD68, CD31 and they sometimes express CD15.5,19 Unlike other histiocytic disorders, the lesional cells in RDD are negative for CD1a.5,19,20 Depending on the clinical scenario and location of the lesion, the differential diagnosis of RDD in cytologic material would include Langerhans cell histiocytosis (LCH), primary or metastatic carcinoma, malignant melanoma, Hodgkin’s lymphoma, xanthoma, and various inflammatory and infectious processes. LCH is characterized by a population of cells with grooved nuclei showing CD1a immunoreactivity and an inconstant but sometimes prominent second population of eosinophils.6,21,22 Primary or metastatic malignancies are cytologically characterized by significant atypia including increased nuclear-tocytoplasmic ratios, nuclear enlargement, prominent nucleoli and nuclear hyperchromasia. Keratin positivity should help in the diagnosis of primary or metastatic carcinomas, while melanomas should be positive for markers of melanocytic differentiation such as Melan-A and HMB45. The aspirate smears in Hodgkin’s lymphoma usually contain typical Reed–Sternberg cells and mononuclear Hodgkin cells in a background of lymphocytes and reactive cells including eosinophils and plasma cells. Although the Reed–Sternberg cells can be large, they usually contain large, multilobated nuclei with coarse chromatin and a prominent nucleolus surrounded by a clear halo. Emperipolesis is not a feature of this entity. Immunoperoxidase stains can be helpful since CD15 and CD30 would highlight the Reed–Sternberg cells which should be negative for CD68 and S100 protein. Xanthomas can present in the GI tract, mainly in the stomach but they have been rarely reported in the rectosigmoid area.23 GI xanthomas usually involve the lamina propria and not the submucosa.23,24 These lesions are composed of small to intermediate sized histiocytes with foamy cytoplasm and small, round nuclei expressing CD68 but not S100 protein. Their cytologic features include cell debris and pigment free histiocytes with foamy cytoplasm while emperipolesis is not present. Infectious processes are usually associated with epithelioid histiocytes characterized by the presence of loosely cohesive clusters of cells with elongated and twisted nuclei displaying fine granular chromatin and pale cytoplasm with indistinct borders.

The pathogenesis of RDD is still unclear, but it has been suggested that it represents a dysfunction of the immune system.6 In cutaneous RDD, the presence of abundant IgG4-positive plasma cells has been hypothesized to be a link to IgG4-related sclerosing disease.25 Only recently, a similar relationship between GI RDD and IgG4-related sclerosing disease has also been implicated in the pathogenesis of nodal and extranodal RDD.26 A treatment for both nodal and extranodal RDD has not yet been determined.7–9,27,28 However, most patients with isolated soft tissue lesions appeared to do well after excisional surgery, although some of them developed recurrence. In summary, RDD rarely involves the GI tract where it can mimic a plethora of other diseases. The submucosal location of the lesions makes them particularly amenable to EUS-FNA and a reliable diagnosis can be provided by cytologic assessment. Given its relatively indolent course, this entity should be kept in mind during FNA of GI tract lesions so that unnecessary patient interventions can be avoided.

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IOANNIDIS ET AL. 14. Hayes MM, Daya H, Uys CJ, Samson RI. Sinus histiocytosis with massive lymphadenopathy: Report of a case associated with necrosis. Arch Pathol Lab Med 1985;109:151–152.

22. Tamiolakis D, Barbagadaki S, Proimos E, et al. Touch imprint cytological diagnosis of nodal Langerhans cell histiocytosis. B-ENT 2009;5:115–118.

15. Brown RD, D’Cruz CA. Sinus histiocytosis with massive lymphadenopathy syndrome: Histogenesis of the hepatic lesion. Ann Clin Lab Sci 1987;17:162–170.

23. Nakasono M, Hirokawa M, Muguruma N, et al. Colorectal xanthomas with polypoid lesion: Report of 25 cases. APMIS 2004;112:3– 10.

16. Milchgrub S, Kamel OW, Wiley E, Vuitch F, Cleary ML, Warnke RA. Malignant histiocytic neoplasms of the small intestine. Am J Surg Pathol 1992;16:11–20. 17. Chak A. EUS in submucosal tumors. Gastrointest Endosc 2002;56: S43–S48.

24. Miliauskas JR. Rectosigmoid (colonic) xanthoma: A report of four cases and review of the literature. Pathology 2002;34:144–147.

18. Vujhini SK, Kolte SS, Satarkar RN, Srikanth S. Fine needle aspiration diagnosis of Rosai-Dorfman disease involving thyroid. J Cytol 2012;29:83–85. 19. McClain KL, Natkunam Y, Swerdlow SH. Atypical cellular disorders. Hematology Am Soc Hematol Educ Program 2004;1:283–296. 20. Slone SP, Fleming DR, Buchino JJ. Sinus histiocytosis with massive lymphadenopathy and Langerhans cell histiocytosis express the cellular adhesion molecule CD31. Arch Pathol Lab Med 2003;127: 341–344. 21. Singhi DA, Montgomery AE. Gastrointestinal tract langerhans cell histiocytosis: A clinicopathologic study of 12 patients. Am J Surg Pathol 2011;35:305–310.

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25. 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. 26. Wimmer DB, Ro JY, Lewis A, et al. Extranodal Rosai-Dorfman disease associated with increased numbers of immunoglobulin g4 plasma cells involving the colon: Case report with literature review. Arch Pathol Lab Med 2013;137:999–1004. 27. Long E, Lassalle S, Cheikh-Rouhou R, Hofman V, Lacour JP, Hofman P. Intestinal occlusion caused by Rosai-Dorfman disease mimicking colonic diverticulitis. Pathol Res Pract 2007;203:233–237. 28. Shukla D, Veillon DM, Abreo F, Cotelingam JD. Pathologic quiz case: A 55-year-old woman with a history of treated Hodgkin disease and a persistent abdominal mass:extranodal gastrointestinal RosaiDorfman disease. Arch Pathol Lab Med 2003;127:1527–1528.

Rectal extranodal Rosai-Dorfman disease diagnosed by EUS-FNA: a case report and review of the literature.

Rosai-Dorfman disease (RDD), also known as "sinus histiocytosis with massive lymphadenopathy," only rarely involves the gastrointestinal (GI) tract. T...
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