International Journal of Gynecological Pathology 33:432–436, Lippincott Williams & Wilkins, Baltimore r 2014 International Society of Gynecological Pathologists
Case Report
Uterine Rosai-Dorfman Disease (Sinus Histiocytosis With Massive Lymphadenopathy) Lorraine Y. Pan, M.D., Saul L. Offman, M.D., Roger A. Warnke, M.D., and Teri A. Longacre, M.D.
Summary: We report a unique case of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) involving the uterus. A 63-yr-old female with a history of parathyroid adenoma and cavernous sinus meningioma underwent total abdominal hysterectomy for a possible uterine malignancy. The histologic findings consisted of a nodular, mass-like infiltration of the myometrium by clusters, cords, and sheets of CD163-positve, S100-positive histiocytes with lymphocytophagocytosis (emperipolesis). The cells were negative for CD1a and langerin. Occasional plasma cells and erythrocytes were also present. Most of the histiocytes had pale, vacuolated, or foamy cytoplasm. In all cases, the nuclei were small and eccentric. No mitotic figures were identified. Two prior cases of Rosai-Dorfman disease have been reported in the female genital tract: 1 in the cervix and 1 in the bilateral ovaries. Rosai-Dorfman disease should be added to the differential diagnosis of histiocyte-rich lesions in the female genital tract. The diagnosis should be strongly considered in the presence of the characteristic histology with lymphocytophagocytosis (emperipolesis). A limited immunohistochemical panel consisting of CD163, S100, and CD1a and/or langerin will confirm the diagnosis in most cases. Key Words: Rosai-Dorfman disease—Sinus histiocytosis with massive lymphadenopathy—Uterus—Histiocytosis.
tract, gastrointestinal tract, liver, pancreas, and head and neck has also been described (3,4). The involvement of the female genital tract is very uncommon (5,6). We report a case of Rosai-Dorfman disease presenting as a uterine mass, review the literature, and discuss clinical manifestations, treatment, and outcome.
Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) is a rare disorder first described in 1969 (1). Affected patients present with massive lymphadenopathy, usually of the cervical region, because of a prominent sinus infiltrate of histiocytic cells that express S100 protein, CD14, CD68, and CD163. Lymphocytophagocytosis or emperipolesis is a characteristic finding (1,2). Although the disease occurs predominantly in the lymph nodes, it can be seen in a variety of extranodal sites, including the skin, soft tissue, upper respiratory tract, and bones (3). Involvement of the urogenital
CASE PRESENTATION A 63-yr-old gravida 2, para 2 female with a history of parathyroid adenoma and cavernous sinus meningioma underwent total abdominal hysterectomy, following a PET scan that depicted a possible uterine malignancy. The intact uterus weighed 90 g. The endometrium was pale-tan, 0.2 cm in thickness, and without abnormality. A poorly circumscribed nodule was present in the myometrium, measuring 2.0 cm in
From the Department of Surgical Pathology, Stanford University School of Medicine, Stanford, California. The authors declare no conflict of interest. Address correspondence and reprint requests to Teri A. Longacre, MD, Stanford University School of Medicine, Room L215, 300 Pasteur Dr., Stanford, CA 94305. E-mail: longacre@ stanford.edu.
DOI: 10.1097/PGP.0b013e3182a03d23
432
UTERINE ROSAI-DORFMAN DISEASE diameter. Histologic sections showed an irregular, sheet-like proliferation of loosely cohesive histiocytic cells dissecting through the bundles of myometrial smooth muscle (Figs. 1, 2) and focally encroaching on the endometrium. In some areas, aggregates of the histiocytic cells also appeared to involve lymphatic spaces (Fig. 3). The cells had small, angulated nuclei, and abundant vacuolated cytoplasm. Scattered lymphocytes and occasional plasma cells were observed within the cytoplasm of the histiocytes (emperipolesis), many of which were separated by a clear halo (Fig. 1). In contrast to the typical Rosai-Dorfman disease, plasma cells were few in number. No mitoses were present. Paraffin sections were stained with hematoxylin and eosin. Immunohistochemical stains for CD68 (clone KP1, 1:1600), CD163 (Novocastra-Leica, Clone 10D6, 1:100), S100 protein (Dako, 1:1000), desmin (Dako, Clone D33, 1:40), cytokeratin mix (50% CAM 5.2 Becton-Dickinson, 1:50, and 50% AE1/AE3, Dako, 1:50), langerin (clone 12D6, Novocastra, 1:200), and HMB45 (clone HMB451, Leica 1:40) were performed. The cells were strongly reactive for CD68 and CD163, confirming histiocytic differentiation and positive for S100 protein (Figs. 2B, 3C). The cells were negative for CD1a, langerin, HMB45, and cytokeratin mix. A desmin immunohistochemical stain highlighted the smooth muscle and provided a negative image of the histiocytic areas. DISCUSSION The initial descriptions of Rosai-Dorfman disease predominantly involved the cervical lymph nodes bilaterally, with spontaneous regression in most cases (sinus histiocytosis with massive lymphadenopathy). Extranodal manifestations, which may occur in 30% to 40% of cases, often mimic a malignant tumor.
433
Extranodal disease is associated with increased propensity for recurrent or progressive disease, and multiorgan involvement has been reported. Involvement of the skin and soft tissue, nasal cavity and paranasal sinuses, and bone accounts for roughly 40% of Rosai-Dorfman disease. Involvement of the central nervous system is often dural-based and clinically and radiologically resembles meningiomas (7). Affected patients may present with low-grade fever, leukocytosis, increased erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Although early reports showed a predilection for individuals below the age of 20 yr, Rosai-Dorfman disease can be encountered in any age group (3). Rosai-Dorfman disease is extremely rare in the female genital tract, with only 2 prior reported cases, 1 involving the cervix and the other involving bilateral ovaries (5,6). The cervical lesion occurred in a 37-yr-old gravida 3, para 3 female with menorrhagia and mild weight loss (5). Hysterectomy revealed a 3 5 cm submucosal mass in the endocervical canal. Although the length of follow-up was limited (24 mo), the patient had an uneventful postoperative course. The second case occurred in a 17-yr-old with primary meningeal Rosai-Dorfman disease at age 12 with multiple recurrent spinal cord lesions at ages 13 and 16, despite radiation (6). She had a long-standing ventriculoperitoneal shunt before developing bilateral ovarian masses. The authors suggested that the ovarian involvement may have been caused by the implantation of cells from the central nervous system via the shunt, because histiocytes were present in the abdominal washing cytologic specimens. The patient reported in our case had a prior clinical and radiologic diagnosis of a cavernous sinus meningioma; however, as it has not been biopsied, the possibility of Rosai-Dorfman disease mimicking a cavernous sinus meningioma
FIG. 1. Cords and sheets of histiocytic cells are seen dissecting through the uterine smooth muscle bundles (A). The cells have small, angulated nuclei, and pale cytoplasm; occasional lymphocytes and plasma cells are admixed (B). Lymphocytophagocytosis is present (C). Note occasional intracytoplasmic plasma cells.
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FIG. 2. The myometrium is diffusely infiltrated by clusters of histiocytes with abundant clear or foamy cytoplasm with small, round, and eccentric nuclei (A). The cells show strong cytoplasmic reactivity for S100 protein (B).
cannot be completely excluded. In either case, no apparent shunt was operative in this case. As most cases of Rosai-Dorfman disease follow a benign clinical course, most patients require no therapy. However, surgical resection is indicated if there is concern for the impaired function of vital organs. Locoregional control has been associated with surgical excision with clear margins. Radiotherapy has been reported to show limited efficacy, whereas chemotherapy is generally ineffective, although the role of immunomodulators has not been well investigated (8). The etiology of Rosai-Dorfman disease is unknown. Infectious agents have been considered, but as yet no organism has been implicated. Affected patients do not appear to have an underlying immune deficiency. The differential diagnosis of the Rosai-Dorfman disease includes a variety of infectious, inflammatory, and neoplastic disorders (Table 1). Xanthogranulomatous inflammation involving the uterus is typically centered in the endometrium but may extend into the
myometrium. In addition to histiocytes, there are admixed neutrophils, plasma cells, lymphocytes, and hemosiderin-laden histiocytes (9–11). In addition, there may be foci of necrosis, cholesterol clefts, or dystrophic calcification. Reactive xanthogranulomatous inflammation may occur secondary to cervical obstruction, radiation, or ablation therapy (11). Mycobacterial and fungal infections may also result in a histiocytic infiltrate; however, the inflammatory process is centered in the endometrium and granulomas are often an additional feature (12,13). Malakoplakia is distinguished by the presence of characteristic Michaelis-Gutmann bodies and intracellular bacilli (14–16). Langerhans cell histiocytosis can rarely occur in the female genital tract; admixed eosinophils are typically present, and the neoplastic Langerhans cells exhibit characteristic longitudinal nuclear grooves and express langerin, CD1a, and S100 protein (17,18). Erdheim-Chester disease is extraordinarily rare and has not been described in the uterus (19). Considered a variant of juvenile
FIG. 3. Aggregates of histiocytes are present in lymphatic spaces in the endometrial basalis (A). The cells have abundant pale cytoplasm with emperipolesis (B). The clusters of histiocytes have moderate to strong reactivity for S100 protein (C).
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TABLE 1. Differential diagnosis of histiocytic proliferations in female genital tract Histiocytic disorder
Histologic features
CD68
CD163
Histiocytes with abundant, clear, somewhat granular cytoplasm; emperipolesis; plasma cell infiltrate; uniformly round, vesicular nuclei Histiocytes with less-abundant cytoplasm, tends to be eosinophilic rather than clear with distinct cell membrane; longitudinal nuclear grooves; admixed eosinophils Dense fibrosis, admixed Touton-type giant cells, lipid vacuoles
+
+
+
–
–
Prior reported female genital tract sites: the ovary and cervix
+
+
+
+
+
May be isolated or multisystem; female genital tract-site involvement is predominantly the vulva, vagina, and cervix
+
+
– /+
–
–
+
+
– /+
–
–
The central nervous system, bone, skin; female genital tract involvement not reported Mass lesion; female genital tractsite involvement is predominantly the cervix
+/ –
+/ –
+
–
–
+
+
–
–
–
+
+
–
–
–
Centered in endometrium
+
+
–
–
–
History of prior cesarean section
+
Unknown
–
–
–
Centered in endometrium
+
+
–
–
–
Genital tuberculosis typically occurs in women from endemic regions
+
+
–
–
—
+
+
–
–
–
May be isolated or multisystem
+
+
–
–
–
Idiopathic granulomas Epithelioid, noncaseating granulomas, often close to thin-walled vessels
+
+
–
–
–
Systemic storage disease
+
+
–
–
–
Female genital tract involvement rare Female genital tract involvement, predominantly the ovary, myometrium, and cervical stroma Female genital tract involvement not reported
Rosai-Dorfman disease Langerhans cell histiocytosis
Erdheim-Chester disease Histiocytic sarcoma
Interdigitating dendritic cell sarcoma Reactive xanthogranulomatous inflammation Malakoplakia Myometrial xanthomatosis Nodular histiocytic hyperplasia Mycobacterial Fungal Giant cell arteritis Sarcoid
Eosinophilic cytoplasm, hemophagocytosis; large, eccentric nuclei, commonly with large multinucleated forms Spindled to ovoid cells in fascicular and storiform patterns; eosinophilic cytoplasm, elongated nuclei Mixed inflammatory response, including neutrophils, plasma cells, lymphocytes, hemosiderin-laden histiocytes Michaelis-Gutmann bodies, intracellular bacilli Clusters, cords, sheets of histiocytes without other inflammatory component Amphophilic cytoplasm; lobulated, reniform nuclei Often with granulomatous inflammation Often with granulomatous inflammation Granulomatous inflammation centered in the small arterial blood vessels with intimal fibrosis Epithelioid, noncaseating granulomas
The presence of accumulated material in cytoplasm (lipid, mucopolysaccharides)
S100 CD1a Langerin
Other features
Usually presents as lymphadenopathy; female genital tract involvement not reported Centered in endometrium; often associated with cervical stenosis, prior procedures
+ indicates vast majority of case positive; +/ – , many cases positive; – /+, occasional cases positive; – , vast minority of cases negative.
xanthogranuloma, the histiocytes in this disease are typically surrounded by dense fibrosis. Admixed Touton-type giant cells may also be present. The histiocytes in Erdheim-Chester disease may express S100 protein but not CD1a (19). Unlike RosaiDorfman disease, numerous lipid vacuoles are often prominent in Erdheim-Chester disease. Uterine tumors resembling sex cord stromal tumors may harbor numerous stromal foam cells; however, additional foci of mesenchymal sex cord-like structures are almost always present (20,21). The histiocytes in the
nodular histiocytic hyperplasia of the endometrium have more lobulated or reniform nuclei, and the cytoplasm is more amphophilic; they are unassociated with other inflammatory cells (22,23). Myometrial xanthomatosis is characterized by a diffuse infiltration of the myometrium by clusters, cords, and sheets of CD163-positive histiocytes with no other significant inflammatory cell component (24). A possible association with prior pregnancy has been suggested. Granular cell tumor may enter the differential diagnosis; however, the constituent cells in this disorder almost always have Int J Gynecol Pathol Vol. 33, No. 4, July 2014
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abundant, eosinophilic granular cytoplasm, and emperipolesis is absent. Finally, storage disorders may also be considered, but in almost all such cases the diagnosis has been previously established and solid organ involvement is secondary. In summary, we report an unusual case of RosaiDorfman disease involving the uterus. Only 2 prior cases of involvement of the female genital tract have been reported, one of which was associated with an intracranial lesion and ventriculoperitoneal shunt, suggesting possible secondary seeding of the involved (ovarian) pelvic organs. The other case appeared to represent a primary occurrence in the cervix. RosaiDorfman disease should be added to the differential diagnosis of histiocyte-rich lesions in the female genital tract. The diagnosis should be strongly considered in the presence of the characteristic histology with lymphocytophagocytosis (emperipolesis). A limited immunohistochemical panel consisting of CD163, S100, and CD1a and/or langerin will confirm the diagnosis in most cases. REFERENCES 1. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinicopathological entity. Arch Pathol 1969;87:63–70. 2. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a pseudolymphomatous benign disorder. Analysis of 34 cases. Cancer 1972;30:1174–88. 3. Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol 1990;7:19–73. 4. Lauwers GY, Perez-Atayde A, Dorfman RF, et al. The digestive system manifestations of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy): review of 11 cases. Hum Pathol 2000;31:380–5. 5. Murray J, Fox H. Rosai-Dorfman disease of the uterine cervix. Int J Gynecol Pathol 1991;10:209–13. 6. Yamaguchi M, Yahata T, Fujita K, et al. Extranodal RosaiDorfman disease involving bilateral ovaries in a patient with a ventriculoperitoneal shunt. J Obstet Gynaecol Res 2009;35:1000–3.
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7. Zhang JT, Tian HJ, Lang SY, et al. Primary intracerebral Rosai-Dorfman disease. J Clin Neurosci 2010;17:1286–8. 8. Pulsoni A, Anghel G, Falcucci P, et al. Treatment of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): report of a case and literature review. Am J Hematol 2002;69:67–71. 9. Blanco C, Fernandez F, Buelta L, et al. Xanthomatous endometritis. Appl Pathol 1989;7:273–6. 10. Ladefoged C, Lorentzen M. Xanthogranulomatous inflammation of the female genital tract [see comments]. Histopathology 1988;13:541–51. 11. Colgan TJ, Shah R, Leyland N. Post-hysteroscopic ablation reaction: a histopathologic study of the effects of electrosurgical ablation. Int J Gynecol Pathol 1999;18:325–31. 12. Nogales-Ortiz F, Tarancon I, Nogales FJ. The pathology of female genital tuberculosis. A 31-year study of 1436 cases. Obstet Gynecol 1979;53:422–8. 13. Bazaz-Malik G, Maheshwari B, Lal N. Tuberculous endometritis: a clinicopathological study of 1000 cases. Br J Obstet Gynaecol 1983;90:84–6. 14. Chen K, Hendricks E. Malakoplakia of the female genital tract. Obstet Gynecol 1985;65:84S–7S. 15. Kawai K, Fukuda K, Tsuchiyama H. Malacoplakia of the endometrium. An unusual case studied by electron microscopy and a review of the literature. Acta Pathol Jpn 1988;38:531–40. 16. Thomas WJ, Sadeghieh B, Fresco R, et al. Malacoplakia of the endometrium, a probable cause of postmenopausal bleeding. Am J Clin Pathol 1978;69:637–41. 17. Montero AJ, Diaz-Montero CM, Malpica A, et al. Langerhans cell histiocytosis of the female genital tract: a literature review. Int J Gynecol Cancer 2003;13:381–8. 18. Sholl LM, Hornick JL, Pinkus JL, et al. Immunohistochemical analysis of langerin in Langerhans cell histiocytosis and pulmonary inflammatory and infectious diseases. Am J Surg Pathol 2007;31:947–52. 19. Dickson BC, Pethe V, Chung CT, et al. Systemic ErdheimChester disease. Virchows Arch 2008;452:221–7. 20. Baker RJ, Hildebrandt RH, Rouse RV, et al. Inhibin and CD99 (MIC2) expression in uterine stromal neoplasms with sex-cord-like elements. Hum Pathol 1999;30:671–9. 21. Clement P, Scully R. Uterine tumors resembling ovarian sexcord tumors. A clinicopathologic analysis of fourteen cases. Am J Clin Pathol 1976;66:512–25. 22. Kim KR, Lee YH, Ro JY. Nodular histiocytic hyperplasia of the endometrium. Int J Gynecol Pathol 2002;21:141–6. 23. Fukunaga M, Iwaki S. Nodular histiocytic hyperplasia of the endometrium. Arch Pathol Lab Med 2004;128:1032–4. 24. Dimaio MA, Longacre TA. Myometrial xanthomatosis: possible relationship to prior pregnancy procedure. Int J Gynecol Pathol 2012;31:166–71.
Case Report
Uterine Rosai-Dorfman Disease (Sinus Histiocytosis With Massive Lymphadenopathy) Lorraine Y. Pan, M.D., Saul L. Offman, M.D., Roger A. Warnke, M.D., and Teri A. Longacre, M.D.
Summary: We report a unique case of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) involving the uterus. A 63-yr-old female with a history of parathyroid adenoma and cavernous sinus meningioma underwent total abdominal hysterectomy for a possible uterine malignancy. The histologic findings consisted of a nodular, mass-like infiltration of the myometrium by clusters, cords, and sheets of CD163-positve, S100-positive histiocytes with lymphocytophagocytosis (emperipolesis). The cells were negative for CD1a and langerin. Occasional plasma cells and erythrocytes were also present. Most of the histiocytes had pale, vacuolated, or foamy cytoplasm. In all cases, the nuclei were small and eccentric. No mitotic figures were identified. Two prior cases of Rosai-Dorfman disease have been reported in the female genital tract: 1 in the cervix and 1 in the bilateral ovaries. Rosai-Dorfman disease should be added to the differential diagnosis of histiocyte-rich lesions in the female genital tract. The diagnosis should be strongly considered in the presence of the characteristic histology with lymphocytophagocytosis (emperipolesis). A limited immunohistochemical panel consisting of CD163, S100, and CD1a and/or langerin will confirm the diagnosis in most cases. Key Words: Rosai-Dorfman disease—Sinus histiocytosis with massive lymphadenopathy—Uterus—Histiocytosis.
tract, gastrointestinal tract, liver, pancreas, and head and neck has also been described (3,4). The involvement of the female genital tract is very uncommon (5,6). We report a case of Rosai-Dorfman disease presenting as a uterine mass, review the literature, and discuss clinical manifestations, treatment, and outcome.
Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) is a rare disorder first described in 1969 (1). Affected patients present with massive lymphadenopathy, usually of the cervical region, because of a prominent sinus infiltrate of histiocytic cells that express S100 protein, CD14, CD68, and CD163. Lymphocytophagocytosis or emperipolesis is a characteristic finding (1,2). Although the disease occurs predominantly in the lymph nodes, it can be seen in a variety of extranodal sites, including the skin, soft tissue, upper respiratory tract, and bones (3). Involvement of the urogenital
CASE PRESENTATION A 63-yr-old gravida 2, para 2 female with a history of parathyroid adenoma and cavernous sinus meningioma underwent total abdominal hysterectomy, following a PET scan that depicted a possible uterine malignancy. The intact uterus weighed 90 g. The endometrium was pale-tan, 0.2 cm in thickness, and without abnormality. A poorly circumscribed nodule was present in the myometrium, measuring 2.0 cm in
From the Department of Surgical Pathology, Stanford University School of Medicine, Stanford, California. The authors declare no conflict of interest. Address correspondence and reprint requests to Teri A. Longacre, MD, Stanford University School of Medicine, Room L215, 300 Pasteur Dr., Stanford, CA 94305. E-mail: longacre@ stanford.edu.
DOI: 10.1097/PGP.0b013e3182a03d23
432
UTERINE ROSAI-DORFMAN DISEASE diameter. Histologic sections showed an irregular, sheet-like proliferation of loosely cohesive histiocytic cells dissecting through the bundles of myometrial smooth muscle (Figs. 1, 2) and focally encroaching on the endometrium. In some areas, aggregates of the histiocytic cells also appeared to involve lymphatic spaces (Fig. 3). The cells had small, angulated nuclei, and abundant vacuolated cytoplasm. Scattered lymphocytes and occasional plasma cells were observed within the cytoplasm of the histiocytes (emperipolesis), many of which were separated by a clear halo (Fig. 1). In contrast to the typical Rosai-Dorfman disease, plasma cells were few in number. No mitoses were present. Paraffin sections were stained with hematoxylin and eosin. Immunohistochemical stains for CD68 (clone KP1, 1:1600), CD163 (Novocastra-Leica, Clone 10D6, 1:100), S100 protein (Dako, 1:1000), desmin (Dako, Clone D33, 1:40), cytokeratin mix (50% CAM 5.2 Becton-Dickinson, 1:50, and 50% AE1/AE3, Dako, 1:50), langerin (clone 12D6, Novocastra, 1:200), and HMB45 (clone HMB451, Leica 1:40) were performed. The cells were strongly reactive for CD68 and CD163, confirming histiocytic differentiation and positive for S100 protein (Figs. 2B, 3C). The cells were negative for CD1a, langerin, HMB45, and cytokeratin mix. A desmin immunohistochemical stain highlighted the smooth muscle and provided a negative image of the histiocytic areas. DISCUSSION The initial descriptions of Rosai-Dorfman disease predominantly involved the cervical lymph nodes bilaterally, with spontaneous regression in most cases (sinus histiocytosis with massive lymphadenopathy). Extranodal manifestations, which may occur in 30% to 40% of cases, often mimic a malignant tumor.
433
Extranodal disease is associated with increased propensity for recurrent or progressive disease, and multiorgan involvement has been reported. Involvement of the skin and soft tissue, nasal cavity and paranasal sinuses, and bone accounts for roughly 40% of Rosai-Dorfman disease. Involvement of the central nervous system is often dural-based and clinically and radiologically resembles meningiomas (7). Affected patients may present with low-grade fever, leukocytosis, increased erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Although early reports showed a predilection for individuals below the age of 20 yr, Rosai-Dorfman disease can be encountered in any age group (3). Rosai-Dorfman disease is extremely rare in the female genital tract, with only 2 prior reported cases, 1 involving the cervix and the other involving bilateral ovaries (5,6). The cervical lesion occurred in a 37-yr-old gravida 3, para 3 female with menorrhagia and mild weight loss (5). Hysterectomy revealed a 3 5 cm submucosal mass in the endocervical canal. Although the length of follow-up was limited (24 mo), the patient had an uneventful postoperative course. The second case occurred in a 17-yr-old with primary meningeal Rosai-Dorfman disease at age 12 with multiple recurrent spinal cord lesions at ages 13 and 16, despite radiation (6). She had a long-standing ventriculoperitoneal shunt before developing bilateral ovarian masses. The authors suggested that the ovarian involvement may have been caused by the implantation of cells from the central nervous system via the shunt, because histiocytes were present in the abdominal washing cytologic specimens. The patient reported in our case had a prior clinical and radiologic diagnosis of a cavernous sinus meningioma; however, as it has not been biopsied, the possibility of Rosai-Dorfman disease mimicking a cavernous sinus meningioma
FIG. 1. Cords and sheets of histiocytic cells are seen dissecting through the uterine smooth muscle bundles (A). The cells have small, angulated nuclei, and pale cytoplasm; occasional lymphocytes and plasma cells are admixed (B). Lymphocytophagocytosis is present (C). Note occasional intracytoplasmic plasma cells.
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FIG. 2. The myometrium is diffusely infiltrated by clusters of histiocytes with abundant clear or foamy cytoplasm with small, round, and eccentric nuclei (A). The cells show strong cytoplasmic reactivity for S100 protein (B).
cannot be completely excluded. In either case, no apparent shunt was operative in this case. As most cases of Rosai-Dorfman disease follow a benign clinical course, most patients require no therapy. However, surgical resection is indicated if there is concern for the impaired function of vital organs. Locoregional control has been associated with surgical excision with clear margins. Radiotherapy has been reported to show limited efficacy, whereas chemotherapy is generally ineffective, although the role of immunomodulators has not been well investigated (8). The etiology of Rosai-Dorfman disease is unknown. Infectious agents have been considered, but as yet no organism has been implicated. Affected patients do not appear to have an underlying immune deficiency. The differential diagnosis of the Rosai-Dorfman disease includes a variety of infectious, inflammatory, and neoplastic disorders (Table 1). Xanthogranulomatous inflammation involving the uterus is typically centered in the endometrium but may extend into the
myometrium. In addition to histiocytes, there are admixed neutrophils, plasma cells, lymphocytes, and hemosiderin-laden histiocytes (9–11). In addition, there may be foci of necrosis, cholesterol clefts, or dystrophic calcification. Reactive xanthogranulomatous inflammation may occur secondary to cervical obstruction, radiation, or ablation therapy (11). Mycobacterial and fungal infections may also result in a histiocytic infiltrate; however, the inflammatory process is centered in the endometrium and granulomas are often an additional feature (12,13). Malakoplakia is distinguished by the presence of characteristic Michaelis-Gutmann bodies and intracellular bacilli (14–16). Langerhans cell histiocytosis can rarely occur in the female genital tract; admixed eosinophils are typically present, and the neoplastic Langerhans cells exhibit characteristic longitudinal nuclear grooves and express langerin, CD1a, and S100 protein (17,18). Erdheim-Chester disease is extraordinarily rare and has not been described in the uterus (19). Considered a variant of juvenile
FIG. 3. Aggregates of histiocytes are present in lymphatic spaces in the endometrial basalis (A). The cells have abundant pale cytoplasm with emperipolesis (B). The clusters of histiocytes have moderate to strong reactivity for S100 protein (C).
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TABLE 1. Differential diagnosis of histiocytic proliferations in female genital tract Histiocytic disorder
Histologic features
CD68
CD163
Histiocytes with abundant, clear, somewhat granular cytoplasm; emperipolesis; plasma cell infiltrate; uniformly round, vesicular nuclei Histiocytes with less-abundant cytoplasm, tends to be eosinophilic rather than clear with distinct cell membrane; longitudinal nuclear grooves; admixed eosinophils Dense fibrosis, admixed Touton-type giant cells, lipid vacuoles
+
+
+
–
–
Prior reported female genital tract sites: the ovary and cervix
+
+
+
+
+
May be isolated or multisystem; female genital tract-site involvement is predominantly the vulva, vagina, and cervix
+
+
– /+
–
–
+
+
– /+
–
–
The central nervous system, bone, skin; female genital tract involvement not reported Mass lesion; female genital tractsite involvement is predominantly the cervix
+/ –
+/ –
+
–
–
+
+
–
–
–
+
+
–
–
–
Centered in endometrium
+
+
–
–
–
History of prior cesarean section
+
Unknown
–
–
–
Centered in endometrium
+
+
–
–
–
Genital tuberculosis typically occurs in women from endemic regions
+
+
–
–
—
+
+
–
–
–
May be isolated or multisystem
+
+
–
–
–
Idiopathic granulomas Epithelioid, noncaseating granulomas, often close to thin-walled vessels
+
+
–
–
–
Systemic storage disease
+
+
–
–
–
Female genital tract involvement rare Female genital tract involvement, predominantly the ovary, myometrium, and cervical stroma Female genital tract involvement not reported
Rosai-Dorfman disease Langerhans cell histiocytosis
Erdheim-Chester disease Histiocytic sarcoma
Interdigitating dendritic cell sarcoma Reactive xanthogranulomatous inflammation Malakoplakia Myometrial xanthomatosis Nodular histiocytic hyperplasia Mycobacterial Fungal Giant cell arteritis Sarcoid
Eosinophilic cytoplasm, hemophagocytosis; large, eccentric nuclei, commonly with large multinucleated forms Spindled to ovoid cells in fascicular and storiform patterns; eosinophilic cytoplasm, elongated nuclei Mixed inflammatory response, including neutrophils, plasma cells, lymphocytes, hemosiderin-laden histiocytes Michaelis-Gutmann bodies, intracellular bacilli Clusters, cords, sheets of histiocytes without other inflammatory component Amphophilic cytoplasm; lobulated, reniform nuclei Often with granulomatous inflammation Often with granulomatous inflammation Granulomatous inflammation centered in the small arterial blood vessels with intimal fibrosis Epithelioid, noncaseating granulomas
The presence of accumulated material in cytoplasm (lipid, mucopolysaccharides)
S100 CD1a Langerin
Other features
Usually presents as lymphadenopathy; female genital tract involvement not reported Centered in endometrium; often associated with cervical stenosis, prior procedures
+ indicates vast majority of case positive; +/ – , many cases positive; – /+, occasional cases positive; – , vast minority of cases negative.
xanthogranuloma, the histiocytes in this disease are typically surrounded by dense fibrosis. Admixed Touton-type giant cells may also be present. The histiocytes in Erdheim-Chester disease may express S100 protein but not CD1a (19). Unlike RosaiDorfman disease, numerous lipid vacuoles are often prominent in Erdheim-Chester disease. Uterine tumors resembling sex cord stromal tumors may harbor numerous stromal foam cells; however, additional foci of mesenchymal sex cord-like structures are almost always present (20,21). The histiocytes in the
nodular histiocytic hyperplasia of the endometrium have more lobulated or reniform nuclei, and the cytoplasm is more amphophilic; they are unassociated with other inflammatory cells (22,23). Myometrial xanthomatosis is characterized by a diffuse infiltration of the myometrium by clusters, cords, and sheets of CD163-positive histiocytes with no other significant inflammatory cell component (24). A possible association with prior pregnancy has been suggested. Granular cell tumor may enter the differential diagnosis; however, the constituent cells in this disorder almost always have Int J Gynecol Pathol Vol. 33, No. 4, July 2014
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abundant, eosinophilic granular cytoplasm, and emperipolesis is absent. Finally, storage disorders may also be considered, but in almost all such cases the diagnosis has been previously established and solid organ involvement is secondary. In summary, we report an unusual case of RosaiDorfman disease involving the uterus. Only 2 prior cases of involvement of the female genital tract have been reported, one of which was associated with an intracranial lesion and ventriculoperitoneal shunt, suggesting possible secondary seeding of the involved (ovarian) pelvic organs. The other case appeared to represent a primary occurrence in the cervix. RosaiDorfman disease should be added to the differential diagnosis of histiocyte-rich lesions in the female genital tract. The diagnosis should be strongly considered in the presence of the characteristic histology with lymphocytophagocytosis (emperipolesis). A limited immunohistochemical panel consisting of CD163, S100, and CD1a and/or langerin will confirm the diagnosis in most cases. REFERENCES 1. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinicopathological entity. Arch Pathol 1969;87:63–70. 2. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: a pseudolymphomatous benign disorder. Analysis of 34 cases. Cancer 1972;30:1174–88. 3. Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol 1990;7:19–73. 4. Lauwers GY, Perez-Atayde A, Dorfman RF, et al. The digestive system manifestations of Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy): review of 11 cases. Hum Pathol 2000;31:380–5. 5. Murray J, Fox H. Rosai-Dorfman disease of the uterine cervix. Int J Gynecol Pathol 1991;10:209–13. 6. Yamaguchi M, Yahata T, Fujita K, et al. Extranodal RosaiDorfman disease involving bilateral ovaries in a patient with a ventriculoperitoneal shunt. J Obstet Gynaecol Res 2009;35:1000–3.
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