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Rosai-Dorfman disease in the central nervous system with two isolated lesions originated from a single clone: a case report

Abstract

Background

Rosai–Dorfman disease (RDD) is a rare, benign, idiopathic non-Langerhans cell histiocytosis. Cases of RDD in the CNS are extremely rare but lethal. RDD is thought to represent a reactive process. Recent studies proposed a subset of RDD cases that had a clonal nature. However, its clone origin is poorly understood.

Case presentation

We present a rare case of RDD in the CNS with two isolated lesions. These two lesions were removed successively after two operations. No seizure nor recurrence appears to date (2 years follow-up). Morphological and immunohistochemical profiles of these two lesions support the diagnosis of RDD. Based on the whole-exome sequencing (WES) data, we found the larger lesion has a higher tumor mutational burden (TMB) and more driver gene mutations than the smaller lesion. We also found seven common truncal mutations in these two lesions, raising the possibility that they might stem from the same ancestor clone.

Conclusions

Overall, this is the first report about clonal evolution of RDD in the CNS with two isolated lesions. Our findings contribute to the pathology of RDD, and support the notion that a subset of cases with RDD is a clonal histiocytic disorder driven by genetic alterations.

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Background

Rosai–Dorfman disease (RDD) is a rare, idiopathic non-Langerhans cell histiocytosis that affects children and young adults. Histologically, RDD is characterized by the histiocytic proliferation in lymph nodes or extranodal tissues. Immunohistochemical staining shows that lesional histiocytes are CD68+, S-100 +, and CD1a -, with prominent emperipolesis [1]. Cases involving the CNS are extremely rare, but they proved to be fatal due to the position [2]. A retrospective analysis showed that in the period between 1969, when the disease was first described, and 2014, only 210 cases of CNS involvement were reported [3]. RDD is considered as a reactive, nonclonal disorder. However, some evidences support a clonal nature of RDD, at least in a subset of cases [4, 5]. Still, the clone origin of RDD is poorly understood.

We identified a rare case of RDD isolated to CNS with two separate lesions. In order to understand the clone origin, we performed the whole-exome sequencing (WES) and made a comparison between two lesions based on sequencing data. We found the large neoplastic lesion had a higher TMB and more driver genes than the small lesion. Meanwhile, we also found seven common truncal mutations in two lesions, indicated that they might stem from the same ancestor clone. These findings provide new sight into the pathology of RDD and may introduce the option of targeted therapy.

Case presentation

This study is approved by our institutional review board and this patient has signed informed consent.

A 33-year-old Chinese male initially presented with an epileptic seizure. Magnetic resonance imaging (MRI) detected two extra-axial, homogeneous, well-defined, dural-based lesions. The large one is in the left frontotemporal parietal region, and the small one is in the right frontal region. T1-weighted images show isointense and slightly hyperintense signal intensity, and T2-weighted images show isointense with intralesional hypointense foci, obviously uniform enhancement with an enhancing dural tail sign (Fig. 1). This patient was initially diagnosed with multiple convex meningiomas and underwent a craniotomy for resection of the large lesion. After the left lesion was resected, this patient recovered very well and restored normal speech function. We recommended adjuvant hormone therapy or radiotherapy but the patient declined any further treatment until progression was seen on the MRI and the patients suffered from a symptomatic seizure 20 months after surgery. MRI showed the size of the right lesion increased obviously. Then the second craniotomy was taken to remove the right lesion, and the patient recovered again with no neurological deficit. There was no seizure nor tumor recurrence on follow-up so far (2 years follow-up).

Fig. 1
figure1

Radiological findings. A. Axial T1-weighted MRI before the first surgery demonstrates two extra-axial, homogeneous, well-defined, dural-based obviously uniform enhancement lesions, including a large lesion (93mm × 80mm × 38mm) in the left frontotemporal parietal region, and a small lesion (38mm × 35mm × 11mm) in the right frontal region. B. Axial T2-weighted MRI before the first surgery. C. Sagittal T1-weighted MRI before the first surgery. D. 3D reconstruction from images before the first surgery shows the large lesion is rich blood supply which is mainly supplied by the middle meningeal artery. E. Axial T1-weighted MRI shows the right frontal lobe lesion grows obviously (50 mm × 50mm × 25 mm) after 20 months. F. Axial T1-weighted MRI shows that there is no tumor recurred in 12 months after the second surgery

In the sections from the first operation, microscopic examination showed a large number of lymphocytes and plasma cells infiltrated in fibrous tissue scattered large histiocytic cells with abundant cytoplasm. Immunohistochemical staining showed positive for S100, CD68, but negative for CD1a (Fig. 2). Both morphological and immunohistochemical profiles of the left lesion supported the diagnosis of RDD.

Fig. 2
figure2

Histopathology of Rosai-Dorfman disease from the first operation. A. Large histiocytes with emperipolesis (HE, 40×). B. Histiocytes with emperipolesis, immunoreactive for CD68 (40×). C. Histiocytes with emperipolesis, immunoreactive for S-100 (40×). D. Histiocytes with emperipolesis, immunoreactive for CD1a (20×)

Histopathological examination for the sections from the second operation exhibited similar results as the first one (Fig. 3). Histiocytes were the predominant cells and contained abundant pale to vacuolated cytoplasm and mildly pleomorphic vesicular nuclei with multiple prominent nucleoli and emperipolesis.

Fig. 3
figure3

Histopathology of Rosai-Dorfman disease from the second operation. A. Histiocytes with emperipolesis (HE, 40×). B. Large histiocytes with emperipolesis, immunoreactive for S-100 (40×). C. Histiocytes with emperipolesis, immunoreactive for CD68 (40×). D. Histiocytes with low proliferation index, immunoreactive for Ki-67 (40×)

Based on whole exome sequencing (WES) data, we calculated the tumor mutation burden (TMB), obtained driver genes, and performed clonality analysis. The larger (left) neoplastic lesion has a higher TMB (3.06/Mb) and more tumor-driven mutations than the smaller (right) one (1.03/Mb). Four driver gene mutations, including PIK3R2, MED12, SUFU, and SOX2 were found in the larger lesion, while only one tumor-driven mutation (NOTCH2) was found in the smaller lesion. There are seven common truncal mutations in the two lesions (Fig. 4). None of them are driver gene mutations. These mutations rarely appear in other populations, indicating that these two lesions may originate from the same main ancestor clone.

Fig. 4
figure4

Evolution tree in two lesions of Rosai-Dorfman disease

Discussion and conclusions

Historically, RDD has been considered as a reactive, non-clonal, non-neoplastic lesions, self-limited disorder of unknown etiology with few patients have poor outcomes. However, patients with RDD have been reported to undergo malignant transformation to histiocytic sarcoma [6] and high-grade lymphoma [7], which indicates their potential for genomic instability. Recent studies have found several mutations in lesional tissues [8, 9], raising the possibility of a clonal origin in some forms of RDD.

Nowadays, through deep-sequencing, multi-region sequencing, and single-cell sequencing, it is proved that almost every tumor evolution begins with a single normal cell, shares a set of truncal mutations in the normal tissue, transforms and expands to form a tumor mass [10]. If tumor subclones have no differential survival within a population, loss of positive selection would mean that the population evolves neutrally (only mutation and drift are at play). If tumor subclones gradually accumulate mutations and show tumor-driver alterations, they would evolve in a Darwinian fashion with clonal selection, favor the expansion of some lineages over others, lead to clonal lineages diverge, and slowly form distinct subpopulations of neoplastic lesions [11].

In this study, we described a rare case of CNS involvement with two isolated lesions. Based on WES data, we found seven common truncal mutations in two lesions, indicated that these two lesions might stem from the same main ancestor clone. These truncal mutations are all reported for the first time in RDD and none of them are tumor driver genes. Both IFITM2 and MST1 involve in immune response [12, 13]. RECQL5 plays an important part in the maintenance of genome stability [14]. PER3 is a circadian pathway gene and often reported to associate with tumor progression [15, 16]. For KRTAP4-5 and RPTN, there is no direct evidence to support their role in tumorigenesis. In addition, we also found that the large neoplastic lesion had a higher TMB and more driver mutations than the small lesion. We retrieved previous CNS RDD studies and attempted to compare mutation landscape between our case and published data. However, limited data could be found in published studies. Only one case report showed BRAF mutation in a CNS RDD case by using targeted sequencing [17]. Other RDD studies revealed several mutated genes which mainly focused on MAPK/ERK pathway but lesions were not from CNS [4, 8]. These MAPK/ERK pathway related mutations were not found in our case, suggesting RDD might be a heterogeneous histiocytosis. Our data filled the gap in the mutational landscape of CNS RDD.

Our findings support the notion that RDD is a clonal proliferation of histiocytic disorder in a subset of patients. We believe that when no driver mutations emerge, histiocytes would evolve neutrally, show reactive proliferation, and grow more slowly, or even remit spontaneously. However, if driver mutations appeared under the accumulation of mutations, the lesion would evolve in a Darwinian fashion with clonal selection, growth acceleration, and lineages expansion. The more driver mutations gained, the faster the lesion grows. As in our case, the large lesion has a higher TMB and more driver mutations than the small one.

To the best of our knowledge, this is the first report about clonal evolution of RDD in the CNS with two isolated lesions. We confirmed that at least a subset of cases with RDD is a clonal histiocytic disorder driven by genetic alterations. Further genetic studies on RDD should be taken to better characterize its pathogenesis as well as open up potential avenues for therapy.

Availability of data and materials

We carefully documented the patient’s data reported in the article. We will share the de-identified data at the request of other qualified investigators for purposes of scientific research or teaching. To request the data, please contact the corresponding authors.

Abbreviations

RDD:

Rosai–Dorfman disease

CNS:

Central nervous system

WES:

Whole-exome sequencing

TMB:

Tumor mutational burden

MRI:

Magnetic resonance imaging

References

  1. 1.

    Papo M, Cohen-Aubart F, Trefond L, Bauvois A, Amoura Z, Emile JF, et al. Systemic Histiocytosis (Langerhans Cell Histiocytosis, Erdheim-Chester Disease, Destombes-Rosai-Dorfman Disease): from oncogenic mutations to inflammatory disorders. Curr Oncol Rep. 2019;21(7):62. https://doi.org/10.1007/s11912-019-0810-6.

    Article  PubMed  Google Scholar 

  2. 2.

    Petzold A, Thom M, Powell M, Plant GT. Relapsing intracranial Rosai-Dorfman disease. J Neurol Neurosurg Psychiatry. 2001;71(4):538–41. https://doi.org/10.1136/jnnp.71.4.538.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Sandoval-Sus JD, Sandoval-Leon AC, Chapman JR, Velazquez-Vega J, Borja MJ, Rosenberg S, et al. Rosai-Dorfman disease of the central nervous system: report of 6 cases and review of the literature. Med (Baltim). 2014;93(3):165–75. https://doi.org/10.1097/MD.0000000000000030.

    Article  Google Scholar 

  4. 4.

    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. Mod Pathol. 2017;30(10):1367–77. https://doi.org/10.1038/modpathol.2017.55.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Durham BH, Lopez Rodrigo E, Picarsic J, Abramson D, Rotemberg V, De Munck S, et al. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nat Med. 2019;25(12):1839–42. https://doi.org/10.1038/s41591-019-0653-6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Venkataraman G, McClain KL, Pittaluga S, Rao VK, Jaffe ES. Development of disseminated histiocytic sarcoma in a patient with autoimmune lymphoproliferative syndrome and associated Rosai-Dorfman disease. Am J Surg Pathol. 2010;34(4):589–94. https://doi.org/10.1097/PAS.0b013e3181d5ddf8.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Krzemieniecki K, Pawlicki M, Marganska K, Parczewska J. The Rosai-Dorfman syndrome in a 17-year-old woman with transformation into high-grade lymphoma. A rare disease presentation. Ann Oncol. 1996;7(9):977. https://doi.org/10.1093/oxfordjournals.annonc.a010804.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Diamond EL, Durham BH, Haroche J, Yao Z, Ma J, Parikh SA, et al. Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms. Cancer Discov. 2016;6(2):154–65. https://doi.org/10.1158/2159-8290.CD-15-0913.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Shanmugam V, Margolskee E, Kluk M, Giorgadze T, Orazi A. Rosai-Dorfman Disease Harboring an Activating KRAS K117N Missense Mutation. Head Neck Pathol. 2016;10 3:394–9. https://doi.org/10.1007/s12105-016-0709-6.

    Article  Google Scholar 

  10. 10.

    Davis A, Gao R, Navin N. Tumor evolution: linear, branching, neutral or punctuated? Biochim Biophys Acta Rev Cancer. 2017;1867(2):151–61. https://doi.org/10.1016/j.bbcan.2017.01.003.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Turajlic S, Sottoriva A, Graham T, Swanton C. Resolving genetic heterogeneity in cancer. Nat Rev Genet. 2019;20(7):404–16. https://doi.org/10.1038/s41576-019-0114-6.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Cheng J, Jing Y, Kang D, Yang L, Li J, Yu Z, et al. The Role of Mst1 in Lymphocyte Homeostasis and Function. Front Immunol. 2018;9:149. https://doi.org/10.3389/fimmu.2018.00149.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Yanez DC, Ross S, Crompton T. The IFITM protein family in adaptive immunity. Immunology. 2020;159(4):365–72. https://doi.org/10.1111/imm.13163.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Hamadeh Z, Lansdorp P. RECQL5 at the intersection of replication and transcription. Front Cell Dev Biol. 2020;8:324. https://doi.org/10.3389/fcell.2020.00324.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Cadenas C, van de Sandt L, Edlund K, Lohr M, Hellwig B, Marchan R, et al. Loss of circadian clock gene expression is associated with tumor progression in breast cancer. Cell Cycle. 2014;13(20):3282–91. https://doi.org/10.4161/15384101.2014.954454.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Wang X, Yan D, Teng M, Fan J, Zhou C, Li D, et al. Reduced expression of PER3 is associated with incidence and development of colon cancer. Ann Surg Oncol. 2012;19(9):3081–8. https://doi.org/10.1245/s10434-012-2279-5.

    Article  PubMed  Google Scholar 

  17. 17.

    Richardson TE, Wachsmann M, Oliver D, Abedin Z, Ye D, Burns DK, et al. BRAF mutation leading to central nervous system rosai-dorfman disease. Ann Neurol. 2018;84(1):147–52. https://doi.org/10.1002/ana.25281.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank for Qun He, Fei Xu and Jun Liu at GenomiCare Biotechnology (Shanghai) Co. Ltd. for providing supports in bioinformatic analysis.

Funding

No targeted funding reported.

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Authors

Contributions

HWJ, ZHY: study design and sample collection; GPS, WAC, MF: clinical information management; TT, DWL: histopathology examination; HQ, FX: bioinformatic analysis; HWJ, DWL contributed to the interpretation of the results and manuscript writing. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zhenhua Yu or Dawei Liu.

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Ethics approval and consent to participate

This study was approved by the institutional review board of the First Affiliated Hospital of Sun Yat-sen University. The ethical approval was required for the performance of genetic tests. Written consent to participate was obtained from 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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The authors declare that they have no competing financial and non-financial interests.

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Jin, H., Yu, Z., Tian, T. et al. Rosai-Dorfman disease in the central nervous system with two isolated lesions originated from a single clone: a case report. BMC Neurol 21, 352 (2021). https://doi.org/10.1186/s12883-021-02379-2

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Keywords

  • Central Nervous System
  • Clone origin
  • Mutation
  • Rosai–Dorfman disease