A rare case report: Rosai-Dorfman syndrome of the mesorectum mimicking a pelvic malignancy

Introduction

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare usually self-limited type of non-Langerhans histiocytosis that was initially described in 1965 by pathologist, Paul Destombes and established as a distinct clinical entity by Rosai and Dorfman in 1969 (1,2). It is unique from other variety of histiocytosis due to the normal appearance of lymphocytes with emperipolesis or plasma cells residing within macrophage cytoplasm (3). RDD is a rare disorder with a reported prevalence 1:200,000; 100 of which are new cases in the United States annually (4). RDD typically presents in younger populations often clinically presenting with painless bilateral cervical lymphadenopathy, low-grade fever, and unintentional weight loss. Gastrointestinal involvement makes up close to 1% of extranodal cases with less than 20 cases reported worldwide, 3 of which were affecting the rectum (4). Classic immunohistochemistry stains positive for S100, CD68 and CD163 (5,6). Molecular testing becomes important for unresectable disease, especially as newer immunotherapies and targeted therapy emerges. The RAS family of protooncogenes can be useful in diagnosis. Neuroblastoma RAS viral oncogene homolog (NRAS) is a protein guanosine triphosphatase (GTP)-ase that can be found on chromosome 1 (7). The Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene amongst all cancer types, originating from chromosome 12, which is heavily involving in epidermal growth factor regulator hormone signal transduction (8). The status of these RAS mutations is significant as there are directed therapies available for metastatic disease. There are at least 6 various molecular features seen in RDD, with the three most common being v-raf murine sarcoma viral oncogene homolog B1 (BRAF), mitogen-activated protein kinase 1 (MAP2K1) and RAS isoforms such as KRAS and NRAS (7). The molecular features become important when disease is unresectable or multifocal and systemic therapy is being considered. RDD can be autoimmune, familial or malignant however regardless of etiology National Comprehensive Cancer Network (NCCN) guidelines recommend resection for symptomatic unifocal disease (7).

The aim of this study is to present an extremely unusual example of a symptomatic pelvic mass, ultimately discovered to be RDD of the mesorectal lymph nodes following low anterior resection. We present this case in accordance with the CARE reporting checklist (available at https://ales.amegroups.com/article/view/10.21037/ales-23-46/rc).

Case presentation

We present a 62-year-old African American female admitted through the emergency department initially for a symptomatic rectosigmoid mass. She had a past medical history of diabetes, hypothyroidism, and hypertension. She had no family history of any types of cancer. Her social history was negative for any tobacco, alcohol or illicit drugs. Her symptoms consisted of right flank pain, occasional fevers, rectal pain, unintentional 20-pound weight loss, and worsening constipation for several months. Computed tomography (CT) scan of the abdomen and pelvis noted a bulky mass at the rectosigmoid junction with partial obstruction, there were no concerns for distant metastatic disease. On digital rectal exam, she had a normal soft distal anorectum with an abrupt palpable smooth firm stricture at 7 cm with normal mucosa. A magnetic resonance imaging (MRI) with rectal protocol demonstrated a large semi-circumferential posterior mid rectal mass with significant extraluminal component, infiltrating the mesorectum and compromising the mesorectal fascial plane, as well as multiple suspicious lymph nodes in the superior rectal lymphatic chain (Figures 1,2). Initial flexible sigmoidoscopy and mucosal biopsy was negative despite there being an apparent extrinsic compression on the distal rectum (Figure 3). This prompted an endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) of the mass which pathology revealed to be benign smooth muscle tissue. Carcinoembryonic antigen (CEA) level was 1.9. She was presented at multi-disciplinary tumor board (MDTB) and the consensus was to re-attempt biopsy of the mass. Examination under anesthesia with transrectal biopsy again revealed normal pathology. Repeat cross-sectional imaging demonstrated an enlarging mesocolic node amenable to excisional biopsy to facilitate definitive pathologic diagnosis and consideration of neoadjuvant treatment options. The patient remained symptomatic with pelvic discomfort and repeated hospital admissions. She underwent robotic exploration which did note her rectum to be densely fixed posteriorly to the sacral promontory. The mesosigmoid lymph node was excised just below the inferior mesenteric artery. Several periaortic lymph nodes were also sent for pathologic evaluation. Unfortunately, tissue pathology demonstrated reactive follicles with perinodal edema, fat necrosis and chronic inflammation with no carcinoma identified and no definitive diagnosis. Her case was re-examined at MDTB, and the decision was made to proceed with surgical resection. She underwent robotic assisted low anterior resection with diverting loop ileostomy of her rectosigmoid mass. Ureteral catheters were placed. A sub-inferior mesenteric vein, medial to lateral approach was performed for early access to the proximal normal plane prior to entering the reoperative site. Splenic flexure mobilization and total mesorectal excision (TME) was performed which was challenging due to her severely fibrotic and inflamed nature of the posterior tissue planes from desmoplastic reaction. An end to end 29 mm stapled colorectal anastomosis was constructed and a diverting loop ileostomy was performed. Immunohistochemical stains for CD68, CD163, S100 and cyclin D1 were positive, while factor XIIIa stained weakly positive (Figures 4-8). Pathology demonstrated RDD with a 9 cm long circumferential mass involving peri colonic tissue, muscularis propria, submucosa and focally the lamina propria of the mucosa of the rectosigmoid. The regional lymph nodes demonstrated sinusoidal involvement by RDD.

Figure 1 Sagittal image of MRI of the rectum suspicious for a mid-rectal neoplasm, infiltrating the mesorectum and threatening the posterior mesorectal fascial margin. MRI, magnetic resonance imaging.

Figure 2 Axial image of MRI of the rectum suspicious for a mid-rectal neoplasm, infiltrating the mesorectum and threatening the posterior mesorectal fascial margin. MRI, magnetic resonance imaging.

Figure 3 Endoscopic finding of the extrinsic rectal mass.

Figure 4 Histologic features of Rosai-Dorfman disease in rectal specimen; H&E stain shown at 100 microns depicting oval to spindled macrophages present. H&E, hematoxylin and eosin.

Figure 5 JenyH&E stain shown at 100 microns depicting emperipolesis noting phagocytosis of lymphocytes by macrophages. H&E, hematoxylin and eosin.

Figure 6 This image notes a CD163 stain at 100 microns which highlights the macrophages within the tissue.

Figure 7 This S100 stain shown at 200 microns highlights the macrophages within the Rosai-Dorfman disease specimen.

Figure 8 Gross specimen cross sectional image of the posterior mesorectal tumor containing Rosai-Dorfman disease.

The patient has recovered well from surgery with resolution of her obstructive symptoms. She did have hospital admissions for small bowel obstructions post operatively leading up to her ileostomy reversal however since ileostomy reversal has recovered well. She has no other signs or symptoms of the disease in short term follow-up.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

The natural history of RDD is self-limiting and relapsing-remitting. Most of the cases follow a promising course (9,10). Ravindran et al. (5) describe increased expression of factor XIIIa, only identified in 30% of patients, and was associated with increased incidence of multifocal disease. The degree of morbidity is directly related to the mass effect on local tissues. Since the pathogenesis of the disease is unclear and the morbidity dependent on the location, the best treatment strategy has not been established but include resection, steroids, chemotherapy, and radiation therapy (1-4,9). RDD is an idiopathic proliferation of non-Langerhans cell histiocytes postulated to be a reactive inflammatory process (2,5,10). Although the etiology is uncertain, some studies suggest an association with viral infections such as herpes viruses, Epstein-Barr virus, cytomegalovirus, and human immunodeficiency virus (HIV), however this has not been substantiated (5). In addition to a viral etiology, other studies have linked RDD to certain inherited diseases, neoplasms, and autoimmune diseases (2,5-9). Moreover, studies have elucidated genetic mutations in RDD patients which include NRAS, KRAS, MAP2K1, and A-Raf Proto-Oncogene, Serine/Threonine Kinase (ARAF). Given the multiple phenotypes of RDD, there are likely to be multiple genetic pathways, immunologic factors, and infectious agents involved in the pathogenesis of RDD.

Gastrointestinal RDD most often anatomically occurs distal to the pylorus and may cause subacute symptoms with gradual progression, typically in middle-aged females (3). Clinically, patients may be asymptomatic or present with vague constellation of symptoms including abdominal pain, constipation, hematochezia, anemia, or bowel obstruction. The manifestations may be solitary or segmental and with or without associated lymphadenopathy. The diagnosis of RDD relies on clinical history and histopathologic evaluation. Large histiocytes with abundant eosinophilic cytoplasm are characteristic of RDD with large hypochromatic nuclei and prominent nucleoli. The presence of emperipolesis (lymphocytophagocytosis) is an advantageous pathologic finding to diagnosis. Emperipolesis when found in rectal specimens is pathognomonic for RDD however it is important to note it can also be seen in Erdheim-Chester disease, Juvenile xanthogranuloma, or even malignant histiocytosis. While emperipolesis can aid in the diagnosis it is not required on pathology in order to diagnose RDD. On immunohistochemistry, histiocytes in RDD stain positive for S100 and CD68, with variable positivity in CD163 and CD14 (3,8,11).

There is no validated approach to determining the proper treatment for RDD, but 20–50% of cutaneous or nodal RDD cases are self-limiting (4,8,9). Surgical excision may be appropriate for unifocal disease and certainly is treatment of choice in cases of obstruction amenable to resection. Treatment with high dose steroids is reported and has variable responses. Other treatments with possible efficacy include chemotherapy, immunomodulatory therapy, monoclonal antibodies, or radiotherapy and generally require definitive diagnosis prior to implementing (4,11-14).

Our patient was presented with a rectal mass found on imaging with enlarged pelvic and perirectal lymph nodes with significant infiltration of the mesorectum. A primary rectal cancer or sarcoma was expected based on initial imaging, however, diagnosis remained elusive despite repeated clinical examination and biopsy until final pathologic evaluation. This case demonstrates the challenge in diagnosing uncommon extramucosal rectal pathologies, especially with suspected malignancy. The soft issue and nodal inflammatory nodal changes related to RDD in the mesorectum have similar overlap with locally advanced rectal neoplasms and other inflammatory disorders. Although there is no significant data comparing medical treatments, accurate preoperative diagnosis is critical to facilitate patient guidance and surgical alternatives, especially for rectal malignancy where neoadjuvant treatments remain standard of care, and the high morbidity associated with rectal resection.

Conclusions

This case demonstrates a unique example of RDD involving the rectum requiring surgical resection. RDD clinically mimics a myriad of malignancies, but is often self-limiting with a good prognosis. Extra-nodal RDD can be diagnosed with the recognition of histiocytes and emperipolesis on histopathology. There are implicit limitations given the retrospective and individual case report nature of this manuscript. This case summons the importance of the multidisciplinary tumor board discussion and the careful thorough evaluation and contributions by the radiologist, pathologist, oncologist, and surgeon in the diagnosis and treatment of rectal diseases.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://ales.amegroups.com/article/view/10.21037/ales-23-46/rc

Peer Review File: Available at https://ales.amegroups.com/article/view/10.21037/ales-23-46/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ales.amegroups.com/article/view/10.21037/ales-23-46/coif). M.A. has received grants from Stryker, Medtronic, J&J, Conmed, Astellas pharmaceuticals, and LivsMed in the past 36 months. He participates on safety monitoring and/or advisory boards for Proximie, Human Extensions, and Distal Motion in the past 36 months and has been involved in leadership roles for Applied Medical, Proximie and Human Extensions in the past 36 months. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Destombes P. Adenitis with lipid excess, in children or young adults, seen in the Antilles and in Mali. (4 cases). Bull Soc Pathol Exot Filiales 1965;58:1169-75. [PubMed]
2. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinicopathological entity. Arch Pathol 1969;87:63-70. [PubMed]
3. Doglioni C. Rosai-Dorfman disease. A legacy of Professor Rosai that is still not exploited completely. Pathologica 2021;113:388-95. [Crossref] [PubMed]
4. Abla O, Jacobsen E, Picarsic J, et al. Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease. Blood 2018;131:2877-90. [Crossref] [PubMed]
5. Ravindran A, Goyal G, Go RS, et al. Rosai-Dorfman Disease Displays a Unique Monocyte-Macrophage Phenotype Characterized by Expression of OCT2. Am J Surg Pathol 2021;45:35-44. [Crossref] [PubMed]
6. Benson AB, Venook AP, Al-Hawary MM, et al. Rectal Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022;20:1139-67. [Crossref] [PubMed]
7. MedlinePlus. NRAS gene. Medlineplus Genetics. Bethesda, MD, USA: U.S. National Library of Medicine. Available online: https://medlineplus.gov/genetics/gene/nras/#references
8. Zeissig MN, Ashwood LM, Kondrashova O, et al. Next batter up! Targeting cancers with KRAS-G12D mutations. Trends Cancer 2023;9:955-67. [Crossref] [PubMed]
9. Cohen Aubart F, Haroche J, Emile JF, et al. Rosai-Dorfman disease: Diagnosis and therapeutic challenges. Rev Med Interne 2018;39:635-40. [Crossref] [PubMed]
10. Santra G, Das BK, Mandal B, et al. Rosai-Dorfman disease. Singapore Med J 2010;51:e173-5. [PubMed]
11. Lambdin J, Phillips JK, Kima ED, et al. Rosai-Dorfman Disease of the Rectum: Newly Identified Genetic Point Mutations and Robotic Resection. Am Surg 2023;89:2897-9. [Crossref] [PubMed]
12. Li X, Hong Y, An Q, et al. Successful treatment of Rosai-Dorfman disease with low-dose oral thalidomide. JAMA Dermatol 2013;149:992-3. [Crossref] [PubMed]
13. Alqanatish JT, Houghton K, Bond M, et al. Rituximab treatment in a child with rosai-dorfman disease and systemic lupus erythematosus. J Rheumatol 2010;37:1783-4. [Crossref] [PubMed]
14. Sandoval-Sus JD, Sandoval-Leon AC, Chapman JR, et al. Rosai-Dorfman disease of the central nervous system: report of 6 cases and review of the literature. Medicine (Baltimore) 2014;93:165-75. [Crossref] [PubMed]