Multifocal Rosai Dorfman disease and simultaneous endometrioid ovarian cancer: a case report.

A middle-aged Caucasian female patient firstly presented to the ear nose and throat (ENT) department in 2017 with restricted nasal breathing. The patient’s medical history was notable only for a hemithyroidectomy performed during adolescence in Bulgaria due to goiter; there were no other known comorbidities and the family history was unremarkable. She was diagnosed with nasal polyposis and a pansinus surgery was performed. Histopathological examination revealed a lymphocyte- and plasma cell-rich lesion with emperipolesis, consistent with RDD. The patient was subsequently referred to our hemato-oncological department for further evaluation and management. Given the absence of symptoms and lymphadenopathy, a watch-and-wait strategy was adopted. In early 2022, she was referred to our endocrinology department for evaluation of a previously diagnosed latent hyperthyroidism treated with 14 milligrams (mg) of carbimazole. In the interim, she had undergone multiple procedures at other hospitals, including repeat pansinus surgery with partial mastoidectomy and conchotomy, cervical lymph node excision, partial cheek resection, and maxillary sinus fenestration due to left-sided neck swelling. She had also undergone an orbital biopsy via anterior orbitotomy. According to the reports, histology again showed plasma cell- and histiocyte-rich infiltrates, though RDD was not explicitly mentioned. A subsequent skeletal scintigraphy performed externally demonstrated tracer uptake in the facial bones and distal femoral shafts. Thyroid scintigraphy—initiated because of latent hyperthyroidism—revealed hypofunctional areas without features of autoimmune thyroiditis. Upon presentation to our endocrinology department, laboratory testing showed euthyroid function, and carbimazole was discontinued. Repeat thyroid scintigraphy demonstrated mild disseminated autonomy without typical signs of Graves’ disease or focal autonomy. Thyroid biopsy confirmed RDD. On physical examination, no palpable lymphadenopathy was detected; however, inspection revealed swelling of the eyelid and thyroid region. A positron emission tomography–computed tomography (PET–CT) scan showed hypermetabolic RDD manifestations in the following locations: intraorbital, right maxillary sinus, inferior nasal concha, right neck, thyroid extending into the mediastinum, and the medullary space of the lower extremities. In addition, a hypermetabolic left parauterine mass (16.7 × 7.8 cm) with cystic-solid morphology (Fig.  1 ), increased peripheral glucose uptake, and radiological features suspicious for malignancy and a hypermetabolic leftsided parailiac mass was detected. Fig. 1 Positron emission tomography–computed tomography scan. A Tumor mass with cystic-liquid parts in lower abdomen presenting with elevated glucose utilization at the margins. Pathological results revealed an endometriod borderline tumor with transition into a moderate degree endometriod ovarian cancer. B Hypermetabolic mass para-iliacal on the left side. Pathological results revealed RDD Positron emission tomography–computed tomography scan. A Tumor mass with cystic-liquid parts in lower abdomen presenting with elevated glucose utilization at the margins. Pathological results revealed an endometriod borderline tumor with transition into a moderate degree endometriod ovarian cancer. B Hypermetabolic mass para-iliacal on the left side. Pathological results revealed RDD Initially, the patient declined both RDD-specific therapy and surgical intervention, and she did not attend follow-up appointments. Incompliance, particularly the failure to attend scheduled appointments, has been a recurrent issue throughout the course of the disease. She returned to our hemato-oncology department later in the end of 2022 with progressive periorbital and cervical swelling (Fig.  2 ). Complete blood count showed a mild microcytic, hypochromic iron deficiency anemia. Other routine laboratory analyses including liver and renal function tests as well as electrolytes were within normal ranges. Given the malignant imaging features of the parauterine mass, surgical management was prioritized by our gynecology team. Fig. 2 Swelling of the lacrimal gland Swelling of the lacrimal gland A median laparotomy with left adnexectomy and excision of a suspicious left para-iliac lymph node was performed in the beginning of 2023 after multidisciplinary discussion and airway assessment by ENT to ensure safe intubation. Intraoperatively, the tumor measured 25 cm and appeared to originate from the left ovary (Fig.  3 ). Frozen section analysis revealed a borderline ovarian tumor, while the lymph node biopsy showed RDD. The procedure was therefore concluded after the adnexectomy. Fig. 3 Tumor of the left ovary which was detected by positron emission tomography–computed tomography and had shown elevated glucose utilization at the margins. Pathological diagnosis: borderline tumor of the ovary with transition into endometrioid ovarian cancer Tumor of the left ovary which was detected by positron emission tomography–computed tomography and had shown elevated glucose utilization at the margins. Pathological diagnosis: borderline tumor of the ovary with transition into endometrioid ovarian cancer Final pathology reclassified the ovarian lesion as an endometrioid borderline tumor with transition into moderately differentiated endometrioid ovarian carcinoma. A second laparotomy was performed for hysterectomy, right adnexectomy, omentectomy, and para-iliac/para-aortic lymph node sampling. Radical lymphadenectomy was avoided owing to the lack of evidence on its safety in RDD. Final staging was pT1a, pNX, L0, V0, G2, R0. Molecular pathology of the RDD tissue revealed a KRAS mutation. Given the early stage of ovarian carcinoma, no adjuvant chemotherapy was initiated, and the patient was enrolled in tumor-specific follow-up. For RDD, high-dose prednisolone (80 mg daily) was initiated preoperatively to bridge the time until relaparotomy in April of 2023, resulting in temporary reduction of eyelid swelling. After 4 weeks, symptoms worsened, and a 4-day dexamethasone pulse (4 mg daily) was administered. Owing to the KRAS mutation, MEK inhibition with cobimetinib was considered and a corresponding request for cost coverage was submitted to the patient’s health insurance provider, which was approved. Following the dexamethasone pulse, prednisolone was reintroduced and tapered. Owing to hyperglycemia and emerging dysphagia suggesting disease progression, therapy was switched to methotrexate (20 mg subcutaneously weekly) with folic acid rescue (5 mg the following day) and prednisolone (25 mg daily). The patient then discontinued all treatment for several weeks, leading to further clinical progression, including worsening dysphagia and orbital and facial swelling. After complete recovery from the second laparotomy, she agreed to initiate cobimetinib at 60 mg daily in July 2023 (days 1–21 of a 28-day cycle) in accordance with international consensus recommendations. Severe acneiform dermatitis prompted a short discontinuation (2 weeks) of the medication and then a dose reduction to 20 mg for six cycles, followed by an alternating schedule of 40 mg and 20 mg daily since February 2024. The patient remains on this schedule of cobimetinib up to this date with a sustained therapeutic response, evaluated by clinical examination and magnet resonance imaging (MRI). The patient presents regularly (approximately every 6–8 weeks) to the hemato-oncological outpatient clinic for clinical examination and blood sampling. Thus far, she has shown very good tolerability to cobimetinib without any adverse effects. Laboratory tests occasionally revealed very mild lymphocytosis (up to 4.27/nL; reference range 1.22–3.56/nL), as well as mild elevations of lactate dehydrogenase (LDH, 260 U/L; reference range < 247 U/L) and creatine kinase (CK, 503 U/L; reference range < 170 U/L), currently without clinical significance. Whole-body MRI is performed approximately every 6 months, alternating with PET–CT scans twice yearly. The most recent imaging studies demonstrated a good therapeutic response with regressive-to-stable findings in the previously described manifestations. An overview of the patient’s clinical course is presented in Table  1 . Table 1 Overview of the patient’s clinical course over time regarding presentation, investigation, and treatment Timeline Presentation Investigation Treatment 2017 (ENT department, hemato-oncological department) Restricted nasal breathing Nasal polyposis diagnosed by sinonasal endoscopy Pansinus surgery, pathology confirmed RDD, watch-and-wait strategy 2017–2022 (other hospitals) Restricted nasal breathing, orbital, and cervical swelling, latent hyperthyroidism Bone scintigraphy: tracer uptake in facial bones and distal femoral shafts Thyroid scintigraphy: hypofunctional areas without features of autoimmune thyroiditis Pansinus surgery, partial mastoidectomy, conchotomy, cervical lymph node excision, partial cheek resection, maxillary sinus → histology: plasma cell- and histiocyte-rich infiltration February and March 2022 (endocrinology department, hemato-oncology department, OBGYN department) Referral because of latent hyperthyroidism, goiter Orbital and cervical swelling No palpable lymphadenopathy Repeat thyroid scintigraphy: mild disseminated autonomy PET–CT: hypermetabolic RDD manifestations: intraorbital, right maxillary sinus, inferior nasal concha, right neck, thyroid extending into the mediastinum, medullary space of the lower extremities + hypermetabolic left parauterine mass (16.7 × 7.8 cm) and leftsided parailiac hypermetabolic mass Denial of surgical intervention and/or RDD-specific therapy October 2022 Progressive cervical and orbital swelling Airway assessment via ENT Prioritizing of gynecological surgical management January 2023 Leftsided adnexectomy and parailiac lymphnode excision via longitudinal laparotomy January 2023–March 2023 Temporary reduction of orbital swelling after prednisolone therapy, then progressive orbital swelling and dysphagia Frozen section: parauterine mass classified as a borderline tumor, lymphnode classified as RDD, reclassification as moderately differentiated endometrioid ovarian carcinoma 4 weeks of high dose prednisolone (80 mg daily), 4 days of dexamethasone (4 mg) pulse therapy, then reintroduction of prednisolone and tapering to 25 mg daily, addition of methotrexate 20 mg weekly in March 2023 April 2023 Relaparotomy for surgical completion regarding the endometrioid ovarian cancer: hysterectomy, right adnexectomy, omentectomy, and para-iliac/para-aortic lymph node sampling May 2023–June 2023 Progressive cervical and orbital swelling, progressive dysphagia Discontinuation of all therapy through the patient July 2023 Start of cobimetinib treatment 60 mg daily, 28 day cycle August 2023 Development of acneiform dermatitis, clinical regression of cervical and orbital swelling, no dysphagia Whole body MRI approx. every 6 months, alternating PET scans twice yearly, regular laboratory testing Discontinuation of cobimetinib for 2 weeks, and the reintroduction with 20 mg of cobimetinib August 2023—01/2024 Sustained remission 20 mg of cobimetinib February 2024–today Alternating 40 mg and 20 mg of cobimetinib, currently 27th cycle Overview of the patient’s clinical course over time regarding presentation, investigation, and treatment Bone scintigraphy: tracer uptake in facial bones and distal femoral shafts Thyroid scintigraphy: hypofunctional areas without features of autoimmune thyroiditis Referral because of latent hyperthyroidism, goiter Orbital and cervical swelling No palpable lymphadenopathy Repeat thyroid scintigraphy: mild disseminated autonomy PET–CT: hypermetabolic RDD manifestations: intraorbital, right maxillary sinus, inferior nasal concha, right neck, thyroid extending into the mediastinum, medullary space of the lower extremities + hypermetabolic left parauterine mass (16.7 × 7.8 cm) and leftsided parailiac hypermetabolic mass

Rosai Dorfman disease (RDD, also known as Rosai Dorfman Syndrome or Rosai Dorfman Destombes disease) is a rare Non-Langerhans-cell histiocytosis, which is characterized by lymphadenopathy and a wide spectrum of clinical manifestations through accumulation of histiocytes in various places. Approximately 43% of the patients have extranodal manifestations [ 1 ]. RDD was first described by Rosai and Dorfman in 1969 [ 2 ]. RDD is part of the myeloproliferative disorders. Even though it does have features of transformed cells, it is not described as cancer because of a low proliferative index of the histiocytes [ 3 , 4 ]. With an incidence of 1:200,000 cases it is a rare disease [ 5 ]. Patients with RDD are typically young African American children or young adults, who often present with massive cervical lymphadenopathy, but extranodal and cutaneous lesions are also common [ 5 , 6 ]. Histopathologically, RDD is usually characterized by large nucleolated and hypochromatic histiocytes, positivity for S100 protein and emperipolesis [ 7 ]. Emperipolesis is the presence of a viable cell within the cytoplasm of another cell [ 8 ]. Treatment of RDD involves complete surgical resection in patients with unifocal disease, corticosteroids, sirolimus, radiation, immunotherapy, or chemotherapy including anthracyclins and alkaloids in patients with extensive disease. Self-limitation is also possible in patients with mild nodal and/or cutaneous involvement [ 6 , 9 , 10 ]. Targeted therapies such as the mitogen activated protein kinase kinase (MEK) inhibitor Cobimetinib are also used in patients with mutation in the Kirsten rat sarcoma virus (KRAS) gene [ 11 ]. RDD can be associated with autoimmune diseases including lupus erythematodes, autoimmune hemolytic anemia, or juvenile idiopathic arthritis as well as different types of neoplasia [ 1 , 6 , 12 ]. In the following case report, we want to present and discuss the case of a 47-year-old female patient with extensive multifocal RDD of several locations and simultaneous endometrioid ovarian cancer.

When the patient came to our hemato-oncological department in early 2022, the main problem for her was the extensive swelling of the eyes due to RDD of the lacrimal glands, which led to massive discomfort of the eye. Approximately 11% of RDD cases have orbital manifestation [ 6 ]. Head and neck involvement, also including the nasal cavity similar to our patient, has been reported in up to 22% of the patients [ 13 ]. Involvement of the bones is rare and only found in 5–10% of the cases, while manifestation in lymph nodes, similar to our patient, are common (57% of cases) [ 6 ]. The presence of multifocal disease, as found in our patient, is associated with mutations in the KRAS gene of the mitogen-activated protein kinase (MAPK) pathway, which was detected in our patient [ 14 ]. While the exact etiopathogenesis of RDD remains subject of research, the fact that mutations in the KRAS and MAP2K1 gene are mutually exclusive, demonstrating the clonality seen in 33% of the patients with RDD [ 14 ], makes the previous perception that RDD is a reactive and non-neoplastic disorder questionable [ 15 ]. The detection of these mutations in at least a significant number of cases, might indicate that RDD is, in these cases, a neoplastic process [ 7 ]. In the conducted next generation sequencing panel from a biopsy of the lacrimal gland of our patient, not only a KRAS mutation was detected, but also low-level copy number variations (CNVs) of the gene DNA polymerase epsilon, catalytic subunit (POLE). Up to this date, there is no sufficient data concerning a causal association between CNVs in the gene POLE and RDD, but we found one case report of Proskuriakova et al. describing the case of a man with RDD where genetic testing also revealed mutations in the genes POLE and KRAS [ 16 ]. There is only limited data about the association of RDD and cancer, especially gynecological cancer, similar to our case with ovarian cancer. However, an association with neoplasia is known [ 5 ]. Concerning gynecological cancers, there are case reports of simultaneous cutaneous RDD and cervical cancer [ 17 ] and the involvement of RDD of the chest wall after mastectomy as treatment for breast cancer [ 18 ]. RDD can also involve the female genital organs, such as the uterus and the ovaries without concomitant other neoplasias [ 19 , 20 ]. Concerning nongynecological cancers, RDD has been associated with Hodgin’s and non-Hodgkin’s lymphoma [ 21 ], clear cell sarcoma [ 22 ], and has also been reported after bone marrow transplantation and myelodysplastic syndrome [ 23 , 24 ]. Whether or not there is a causal link between RDD and malignancies remains a subject of research. Regarding the simultaneous endometrioid ovarian cancer in our patient, there have been no previous reports on a possible link between ovarian cancer and RDD to our best knowledge. Endometrioid ovarian cancer is often associated with endometriosis and tends to present in an early stage compared with serous cell ovarian cancer [ 25 ]. Our patient had no previous diagnosis of endometriosis. While somatic KRAS mutations are more often seen in patients with mucinous ovarian cancer [ 26 ], endometrioid ovarian cancer is linked to mutations in the AT-rich interactive domain-containing protein 1A ( ARID1A ) gene, a tumor suppressor gene [ 27 , 28 ]. Moreover, our patient did not have any pathological findings in the autoimmune disease panel, which was carried out because of possible simultaneous autoimmune diseases in patients with RDD [ 29 ]. Since a mutation in the KRAS gene of the MAPK pathway was detected in our patient, and because of the extensive extranodal disease in various locations and relapse during treatment with corticosteroids and methotrexate, a therapy with the MEK inhibitor cobimetinib was chosen [ 5 ]. MEK inhibition has shown good preliminary results in patients with KRAS mutation, leading to remission and complete response [ 11 , 30 ]. A phase 2 trial of the use cobimetinib in histiocytotic disorders was completed in December 2022 ( www.clinicaltrials.gov , Identifier: NCT02649972 ), which led to US Food and Drug Administration (FDA) approval [ 31 ]. Previously, a proof of concept study carried out by Diamond et al. showed a response rate of 100% in 18 treated patients with histiocytotic disorders and mutations in the MAPK pathway after 1 year [ 32 ]. While it is proven that extranodal involvement in the rare Rosai Dorfman disease is not uncommon, a possible causal link between RDD and cancer remains a subject of research [ 5 ]. There are case reports of simultaneous cancer and RDD [ 17 , 21 – 23 ]. RDD itself is often described as a reactive process, but since it can be associated with mutations involving the MAPK signaling pathway it could—in these cases—also be described as a neoplastic process [ 7 ]. In our patient, after treating the simultaneous endometrioid ovarian cancer, a treatment with the MEK inhibitor cobimetinib seemed to be the best option for this patient, because of a detected KRAS mutation and extensive disease with involvement of various locations (head and neck region, parailiacal lymph node, lacrimal gland, bone shafts). Further studies with a larger sample size regarding the use and efficacy of cobimetinib in patients with RDD and regarding a possible causal association between cancer and RDD are needed to draw further conclusions.

Additional file 1. Additional file 1.