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An extremely rare case of Rosai-Dorfman disease in the spleen

Abstract

Background

Rosai-Dorfman disease (RDD) is a rare, multisystemic histiocytic disorder, and commonly manifesting as lymphadenopathy in the young male. Abdominal manifestations of RDD are extremely rare.

Case presentation

In August 2018, a 42-year-old man underwent an abdominal ultrasonography examination due to his weight loss of 10 kg in only three months and found a giant solid tumor was found in his spleen. Then, he was admitted to our hospital and diagnosed as a splenic mass via abdominal enhanced CT and MRI. Laparoscopic splenectomy was administrated within six days of admission due to the clear surgical indications. The pathogenesis of RDD remained poorly understood and the disease should be diagnosed based on histopathology and immunohistochemistry (IHC). The mutations in ATM and NFKBIA were observed using next generation sequencing (NGS).

Conclusion

We reported a case of splenic involvement of RDD with NGS genetic testing, indicating the difficulty of making a diagnosis before surgery. This extremely rare case offers new references for the understanding of abdominal viscera RDD.

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Background

Rosai-Dorfman disease (RDD) first described in details by Rosai and Dorfman in 1969, also known as sinus histiocytosis with massive lymphadenopathy (SHML), is generally a rare benign disorder consisting of a proliferation of histiocytes with polytropic clinical manifestations, such as painless lymphadenopathy or extranodal soft tissue massed, fever, weight loss, etc. [1, 2]. RDD can occur at any age and is most commonly seen in young adults and children [3]. It is reported that up to 50% of RDD patients have extranodal manifestations, and almost every organ system can be involved, in which the involvement of gastrointestinal tract is less common [4]. Histologically, lymph nodes appear dilated sinuses and pericapsular fibrosis, infiltrate extensively into histiocytes, lymphocytes, and plasma cells [5]. Immunohistochemically, the proteins like S100 and CD68 are expressed in histiocytes [6]. In detection of RDD-related mutations, the presence of mutually exclusive KRAS and MAP2K1 mutations, which regulated MAPK/ERK signaling pathway, was found in 7 of 21 RDD cases [7]. Herein, we reported a rare case of RDD in the spleen.

Case presentation

A 42-year-old male visited to Tianjin Medical University General Hospital with a chief complaint of weight loss of 10 kg within three months. Physical examination revealed no stained-yellow sclera and no enlarged lymph nodes in the neck, underjaw, armpits, and groin. An enlarged spleen could be palpated in the left upper abdomen, but no tenderness. Abdomen ultrasound suggested that there was a huge mass in the spleen.

The enhanced computerized tomography (CT) and magnetic resonance imaging (MRI) were performed when the patient was admitted to our hospital for the first time. A giant solid tumor of the spleen was considered. The images of the arterial phase (Fig. 1a) and portal phase (Fig. 1b) revealed a huge low-density mass in the spleen with nodular enhancement on the margin. The separations and scattered calcifications could be seen in the spleen, with the maximum cross-section area of 12.1 × 15.1 (cm2). The nearby compressed, displaced tissues and organs had unclear boundaries with the greater curvature of the gastric wall. There were no enlarged lymph nodes in the abdomen and retroperitoneum, and no sign of ascites. The arterial phase of T2 (Fig. 1c) and T1 fat-suppression image (Fig. 1d) showed a huge mass with mixed signals in the spleen, including high signals in the peripheral area of T2 and diffusion-weighted imaging (DWI), and low signals in the central zone of T2 and DWI. Nodular enhancement could be found in the margin of the spleen and enlarged lymph nodes could be seen around. A blood test was used to detect the tumor markers, and the results showed that carbohydrate antigen 199 (CA199), alpha-fetal protein (AFP) and carcinoma embryonic antigen (CEA) were at a normal level but ferritin increased to 596.7 ng/ml.

Fig. 1
figure1

CT/ MRI-scan examinations. Enhanced CT in the upper abdomen: a, b were arterial and portal phases, respectively. Enhanced MRI in the upper abdomen: arterial phase of T2 was revealed in c. T1 fat-suppression images was shown in d

Laparoscopic splenectomy was performed, and the intraoperative specimen was seen in Fig. 2a. The tumor of the spleen was grayish-white and hard, with intact envelope, and the surrounding tissues were not invaded. The postoperative specimen was shown in Fig. 2b. The tumor with a diameter of about 12 cm located in the upper spleen and seemed like spherical. The section was grayish-yellow and the boundary was clear.

Fig. 2
figure2

Specimen of intra-operation (a) and post-operation (b)

Postoperative pathological results via hematoxylin and eosin (H&E) indicated a cross distribution of deeply and lightly stained lesions (Fig. 3a). The deeply stained zone was mainly composed of a large number of plasma cells and lymphocytes, and interspersed in a flake-like, lightly stained area like stripes, which was known as emperipolesis. The giant pleomorphic tissue cells characterized by abundant cytoplasm, vacuoles, large nuclei, and irregular nucleus were distributed in the lightly stained area (Fig. 3b). In the cytoplasm of histiocytes, it could be observed that some lymphocytes and a small number of plasma cells were phagocytized, which was the typical phenomenon known of emperipolesis (Fig. 3c).

Fig. 3
figure3

Pathologic diagnosis of the patient. Observations of cytology: a–c were sections with H&E staining under × 40, × 200, and × 400, respectively. Results of IHC: d and e were S100 and CD68 respectively, and both of them were positive

Immunohistochemically, S‑100 protein staining was strong positive, diffusely distributed within histiocytes in the lesion (Fig. 3d). The labeling for CD68 protein was also positive within the lesioned histiocytes (Fig. 3e). CD1a, CD21, CD23, CK, HMB45, Melanie, SMA, Desmin, EMA, CD31, CD34, Fli-1, FVIII, CD20, and CD3 were negative, and Ki67 index was about 15% in lymphocytes and plasma cells. Therefore, the patient was diagnosed as RDD.

To analyze the molecular character of this case and seek available options of precise treatment, a comprehensive genomic profiling with a 539-genes panel (Simceredx, Nanjing, China) was administered in biopsy specimens via NGS by DNA-based hybrid capture. NGS could detect the potential deleterious and damaging mutations (Table 1). The mutations of ATM and NFKBIA, which were genes associated with apoptosis, were identified (Fig. 4).

Table 1 The gene mutations detected via NGS in the patient with RDD
Fig. 4
figure4

The mutations of ATM and NFKBIA in the patient with RDD. a Deletion mutation of ATM, c.2462delG, p.S821fs. b Missense mutation of ATM, c.3805A>C, p.K1269Q. c Missense mutation of NFKBIA, c.946A>G, p.T316A, respectively

Discussion and conclusions

RDD is a rare histiocytic disorder with unclear mechanisms, which is easy to be misdiagnosed. The typical features of RDD are painless lymphadenectasis in the bilateral neck, usually accompanied by the symptoms such as fever, weight loss, and anemia. According to the location of lesions, RDD could be divided into three types: most commonly lymph node type, extranodal type, and mixed type [8]. As an extranodal subtype, abdominal viscera manifestations are extremely rare in RDD [4].

RDD is still a disorder with unclear etiology. Some researchers thought that RDD was related to virus infections such as human herpesvirus (HHV), human parvovirus B19, and Epstein-Barr virus [9, 10], and human immunodeficiency virus (HIV) and human herpes virus (HHV) had been detected in RDD diseased tissue [11, 12]. Previous studies suggested the pathogenesis of RDD might be associated with monocyte/macrophage colony-stimulating factor (M-CSF) which led to the production of immunosuppressive macrophages and signal transduction by the genome alterations and homeostasis interference [13]. However, it remained controversial about the association of IgG4 with RDD [9]. RDD is considered being an autoimmune disorder due to its frequent coexistence with immune-mediated diseases including asthma, systemic lupus erythematosus, rheumatoid arthritis, and hemolytic anemia [14,15,16]. In our case, the absolute value of monocytes increased, which appeared to support this opinion partially.

Emperipolesis and storiform structure are the hallmark characters of RDD, however, emperipolesis is not pathognomonic [17,18,19]. Therefore, more examinations including IHC and special staining need to be performed to exclude other diseases. The RDD cells are positive for phagocytic markers including S100 and CD68, but not for markers such as CD1a and CD23 [3]. The patient was confirmed as RDD via both histology and IHC techniques. There were two splenic RDD reported before, one was confirmed by imaging [4], the other was diagnosed via pathology [20]. H&E staining of the latter patient showed that trilineage extramedullary hematopoiesis was found to be extensive, which also existed in peripheral lymph nodes. Meanwhile, multifocal S-100 positive histiocytic aggregates were also presented.

The literature review indicates 20% of RDD patients can be self-healing, 70% are in stable condition, only 10% arise have aggressive local lesions or systemic disease [21]. RDD could be fatal for a very small percentage of patients if the giant enlarged lymph nodes compress vital organs, with the combination of mass formation and cellular infiltration [22, 23]. For symptomatic RDD patients or those with involvement of critical organs, the treatments including surgery should be given [9].

The MAPK/ERK is a critical regulatory pathway in various cellular processes, such as cell proliferation, differentiation, survival, and apoptosis [24]. The mutations in KRAS and MAP2K1 genes can activate MAPK/ERK, which are considered to be associated with RDD [7]. In 9 RDD cases undergoing whole exome sequencing, 3 harbor NOTCH1 gene mutations involving in cell apoptosis [25]. Children with RDD have a similar phenotype to autoimmune lymphoproliferative syndrome which is associated with Fas-mediated apoptosis [26]. ATM and NFKBIA genes also play important roles in regulating apoptosis [27, 28]. We speculate that mutations in apoptosis-related genes which could lead to abnormal apoptosis of histiocytes and lymphocytes may be associated with RDD. However, it needs further confirmation in a larger cohort.

To the best of our knowledge, this is the second spleen occurring RDD case with specific proof via histology and IHC, but the first splenic RDD case with analysis of gene mutations. Our findings suggest the difficulty of making a diagnosis before surgery and provide new references for the understanding of abdominal viscera RDD.

Abbreviations

AFP:

Alpha-fetal protein

CA199:

Carbohydrate antigen 199

CEA:

Carcinoma embryonic antigen

CT:

Computerized tomography

DWI:

Diffusion-weighted imaging

H&E:

Hematoxylin and eosin

HHV:

Human herpes virus

HIV:

Human immunodeficiency virus

IHC:

Immunohistochemistry

M-CSF:

Monocyte/macrophage colony-stimulating factor

MRI:

Magnetic resonance imaging

NGS:

Next generation sequencing

RDD:

Rosai-Dorfman disease

SHML:

Sinus histiocytosis with massive lymphadenopathy

References

  1. 1.

    Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinicopathological entity. Arch Pathol. 1969;87:63–70.

    CAS  PubMed  Google Scholar 

  2. 2.

    Xu H, Zhang F, Lu F, Jiang J. Spinal Rosai-Dorfman disease: case report and literature review. Eur Spine J. 2017;26:117–27.

    Article  Google Scholar 

  3. 3.

    Bernácer-Borja M, Blanco-Rodríguez M, Sanchez-Granados JM, Benitez-Fuentes R, Cazorla-Jimenez A, Rivas-Manga C. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): clinico-pathological study of three cases. Eur J Pediatr. 2006;165:536–9.

    Article  Google Scholar 

  4. 4.

    Karajgikar J, Grimaldi G, Friedman B, Hines J. Abdominal and pelvic manifestations of Rosai-Dorfman disease: a review of four cases. Clin Imaging. 2016;40:1291–5.

    Article  Google Scholar 

  5. 5.

    Juskevicius R, Finley JL. Rosai-Dorfman disease of the parotid gland: cytologic and histopathologic findings with immunohistochemical correlation. Arch Pathol Lab Med. 2001;125:1348–50.

    CAS  PubMed  Google Scholar 

  6. 6.

    Pradhananga RB, Dangol K, Shrestha A, Baskota DK. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): a case report and literature review. Int Arch Otorhinolaryngol. 2014;18:406–8.

    Article  Google Scholar 

  7. 7.

    Garces S, Medeiros LJ, Patel KP, Li S, Pina-Oviedo S, Li J, et al. Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease. Modern Pathol. 2017;30:1367.

    CAS  Article  Google Scholar 

  8. 8.

    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.

    CAS  PubMed  Google Scholar 

  9. 9.

    Dalia S, Sagatys E, Sokol L, Kubal T. Rosai-Dorfman disease: tumor biology, clinical features, pathology, and treatment. Cancer Control. 2014;21:322–7.

    Article  Google Scholar 

  10. 10.

    Zhao M, Li C, Zheng J, Yu J, Sha H, Yan M, et al. Extranodal Rosai-Dorfman disease involving appendix and mesenteric nodes with a protracted course: report of a rare case lacking relationship to IgG4-related disease and review of the literature. Int J Clin Exp Pathol. 2013;6:2569.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Elbuluk N, Egbers R, Taube JM, Wang TS. Cutaneous Rosai-Dorfman disease in a patient with human immunodeficiency virus. Dermatol Online J. 2016;22:13030/qt2162h3fj.

  12. 12.

    Arakaki N, Gallo G, Majluf R, Diez B, Arias E, Riudavets MA, et al. Extranodal Rosai-Dorfman disease presenting as a solitary mass with human herpesvirus 6 detection in a pediatric patient. Pediatr Dev Pathol. 2012;15:324–8.

    Article  Google Scholar 

  13. 13.

    Cai Y, Shi Z, Bai Y. Review of Rosai-Dorfman disease: new insights into the pathogenesis of this rare disorder. Acta Haematol. 2017;138:14–23.

    CAS  Article  Google Scholar 

  14. 14.

    Luppi M, Barozzi P, Garber R, Maiorana A, Bonacorsi G, Artusi T, et al. Expression of human herpesvirus-6 antigens in benign and malignant lymphoproliferative diseases. Am J Pathol. 1998;153:815–23.

    CAS  Article  Google Scholar 

  15. 15.

    Meaghann W, Clifford M, Klara G, Sunanda G, Nandini M, Melissa E, et al. Index of suspicion. Case 1: daily fevers, rash, myalgia, arthralgia, and hepatomegaly in a teen-age girl. Case 2: subcutaneous nodules and arthritis in an 11-year-old boy. Case 3: fever, fatigue, cervical lymphadenopathy, and hepatosplenomegaly in a 3-year. Pediatr Rev. 2013;34:137–42.

    Article  Google Scholar 

  16. 16.

    Ha H, Kim KH, Ahn YJ, Kim JH, Kim JE, Yoon S-S. A rare case of Rosai-Dorfman disease without lymphadenopathy. Korean J Intern Med. 2016;31:802–4.

    CAS  Article  Google Scholar 

  17. 17.

    Rastogi V, Sharma R, Misra S, Yadav L, Sharma V. Emperipolesis—a review. J Clin Diagn Res. 2014;8:ZM01–2.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Maia R, de Meis E, Romano S, Dobbin J, Klumb C. Rosai-Dorfman disease: a report of eight cases in a tertiary care center and a review of the literature. Braz J Med Biol Res. 2015;48:6–12.

    CAS  Article  Google Scholar 

  19. 19.

    Chou T-C, Tsai K-B, Lee C-H. Emperipolesis is not pathognomonic for Rosai-Dorfman disease: rhinoscleroma mimicking Rosai-Dorfman disease, a clinical series. J Am Acad Dermatol. 2013;69:1066–7.

    Article  Google Scholar 

  20. 20.

    Knox SK, Kurtin PJ, Steensma DP. Isolated splenic sinus histiocytosis (Rosai-Dorfman disease) in association with myelodysplastic syndrome. J Clin Oncol. 2006;24:4027–8.

    Article  Google Scholar 

  21. 21.

    Duval M, Nguyen V-H, Daniel SJ. Rosai-Dorfman disease: an uncommon cause of massive cervical adenopathy in a two-year-old female. Otolaryngol Head Neck Surg. 2009;140:274–5.

    Article  Google Scholar 

  22. 22.

    Hashimoto K, Kariya S, Onoda T, Ooue T, Yamashita Y, Naka K, et al. Rosai-Dorfman disease with extranodal involvement. Laryngoscope. 2014;124:701–4.

    Article  Google Scholar 

  23. 23.

    Bulyashki D, Brady Z, Arif S, Tsvetkov N, Radev RS. A fatal case of Rosai-Dorfman disease. Clin Case Rep. 2017;5:1407–8.

    Article  Google Scholar 

  24. 24.

    Kolch W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol. 2005;6:827–37.

    CAS  Article  Google Scholar 

  25. 25.

    Fu WJ, Du J, Lu J, et al. Rosai-Dorfman disease: a clinicopathologic analysis and whole exome sequencing in 23 cases. Chin J Hematol. 2019;40:656–61.

    CAS  Google Scholar 

  26. 26.

    Maric I, Pittaluga S, Dale JK, et al. Histologic features of sinus histiocytosis with massive lymphadenopathy in patients with autoimmune lymphoproliferative syndrome. Am J Surg Pathol. 2005;29:903–11.

    Article  Google Scholar 

  27. 27.

    Beauvarlet J, Bensadoun P, Darbo E, et al. Modulation of the ATM/autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells. Nucleic Acids Res. 2019;47:2739–56.

    CAS  Article  Google Scholar 

  28. 28.

    Huang Q, Zhan L, Li J, et al. Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy. 2016;12:999–1014.

    CAS  Article  Google Scholar 

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Acknowledgements

None declared.

Funding

The authors received no financial support for the research, authorship, and publication of this article.

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Authors

Contributions

YXW made major contributions to manuscript writing. SYP and LQ acquired the clinical data. FC, SYP and LQ analyzed and interpreted the data. ZX and DFR performed the NGS analysis. TWJ designed the study. YXW and TWJ performed a critical revision of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Weijun Tian.

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The report of this case was deemed exempt from review by the Tianjin Medical University General Hospital Institutional Review Board (IRB). Informed consent was obtained from the family of the patient.

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Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

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Data supporting the present findings can be obtained, after obtaining permission from the Tianjin Medical University General Hospital. The data can be obtained by corresponding author.

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Yang, X., Fang, C., Sha, Y. et al. An extremely rare case of Rosai-Dorfman disease in the spleen. BMC Surg 21, 24 (2021). https://doi.org/10.1186/s12893-020-01014-0

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Keywords

  • Rosai-Dorfman disease
  • Spleen involvement
  • Laparoscopic splenectomy
  • Histopathology
  • Immunohistochemistry