Common progenitor origin for Rosai-Dorfman disease and clear cell sarcoma.

Histiocytic neoplasms (HNs) in adults have been reported to be associated with a high prevalence of coexisting haematological and solid malignancies. While a proportion of coexisting HNs and haematological malignancies share identical genetic alterations, the genetic association between HNs and solid malignancies has scarcely been reported. We report a case of Rosai-Dorfman disease (RDD) complicated by coexisting clear cell sarcoma (CCS). RDD is a rare HN. CCS is an ultrarare soft tissue sarcoma with a poor prognosis. Mutation analysis with whole-exome sequencing revealed six shared somatic alterations including NRAS p.G12S and TP53 c.559+1G>A in both the RDD and CCS tissue. This is the first evidence of a clonal relationship between RDD and solid malignancies using mutational analysis. We hypothesise that neural crest cells, which originate in CCS, are likely the common cells of origin for RDD and CCS. This case helps to unravel the underlying clinicopathological mechanisms of increased association of solid malignancies in HNs. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Mixed histiocytic disorders: Nature versus nurture?

Histiocytic diseases arise from MAPK mutations in myeloid progenitors. Depending on whether the progenitor follows a dendritic cell or macrophage/monocyte lineage the final histology results in Langerhans cell histiocytosis, Rosai-Dorfman disease or Erdheim-Chester disease. Commentary on: Friedman et al. Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy. Br J Haematol 2024;205:127-137.

Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy.

Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.

Investigating the correlation between small molecular inhibitor utilization, peripheral blood monocytes, and treatment outcomes in Rosai Dorfman disease.

Rosai Dorfman disease (RDD) is a non-Langerhans cell histiocytic neoplasm characterized by sinus histiocytosis with variable emperipolesis. There is a limited understanding of the factors that contribute to disease progression. Traditional management of RDD consists of local therapies (resection, radiation) for localized disease and myelosuppression for systemic disease; targeted medications have also recently been introduced into clinical practice as an additional therapeutic modality. The goals of this study are to compare the impact of targeted therapies to conventional management of RDD and identify trends in laboratory data that may provide insight into disease progression. A retrospective analysis was conducted at a single institution over a 20-year period in 35 adult patients with histopathologic evidence of RDD without confounding secondary malignancies. Clinical data points included laboratory evaluation, molecular diagnostics, imaging, and therapies rendered. Binary data was utilized for statistical analysis and comparison of outcomes by treatment type and utilization of targeted agents. Evaluation of treatment response varied based on anatomic disease sites and baseline imaging modality. To standardize the radiographic analysis, we included PERCIST (if PET was utilized) or RECIST assessments (in the cases of CT or MR imaging). Conventional therapies rendered included local treatment (surgery, radiation, intralesional injections), systemic corticosteroids, immunotherapy, and chemotherapy while targeted agents included only small molecule inhibitors. In this analysis, primary disease was identified in cutaneous, osseous, and CNS structures (17, 11, and 6/35 patients respectively). Management consisted of surgery (12/35 patients), steroid and myelosuppressive therapies (9/35 each), immunotherapy (5/35), and targeted molecular agents (5/35). In evaluating outcomes, the proportion of partial responses was substantially higher in recipients of molecular as compared to conventional therapy (4/5 patients compared to 6/29) while complete responses were more common in the conventional therapy cohort (12/29 compared to 1/5). Lastly, an evaluation of peripheral blood absolute monocytes in all patients who had progressed on therapy identified a significant decrease in pre-progression values as compared to values following therapy re-institution (averages of 0.70 and 0.27 K/µL, respectively; p = 0.0002, 95% CI 0.652-0.2360). Larger-scale studies are needed to further evaluate the relevance of the monocyte trends that were identified in terms of their relationship to disease status. This study is the largest analysis of Rosai Dorfman disease, that we are aware of, from a single institution. In this cohort, the utilization of small molecule inhibitors corresponded to a greater increase in partial responses than conventional therapies, although the opposite effect has been observed in complete responses. This finding can be attributed to the recent introduction of targeted agents and shorter follow-up. We anticipate higher complete response rates with the use of small molecule in ongoing analyses over a longer follow-up period. The recognition of relative monocyte elevation prior to disease progression is an intriguing and to our knowledge, novel finding in the field of Rosai Dorfman disease. Future studies aimed at elucidating the implications of this trend are in progress.

Synchronous occurrence of primary cutaneous B-cell lymphoma and cutaneous Rosai-Dorfman disease in distinct lesions: A unique association.

Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy (SHML), is a rare subtype of reactive histiocytosis which is seldom associated with Hodgkin's and non-Hodgkin's lymphomas. To date, the coexistence in the same patient of extra nodal SHML and primary cutaneous B-cell lymphoma (PCBCL) has been reported in the literature, as metachronous diagnosis in the anatomical area of the original PCBCL or synchronous occurrence in the same lesions. However, no data have been published as for synchronous occurrence of the two pathological entities in distinct anatomical sites. Herein, we report the first ever described synchronous occurrence of PCBCL and SHML, detected in distinct lesions, affecting the same patient. The complete resolution of the patient's PCBCL after rituximab treatment and the concomitant regression of SHML suggest that this clinically benign reactive histiocytic proliferation, potentially triggered by the lymphoma microenvironment itself, may take place not only in the site of the PCBCL lesion, but also in other distant areas not directly affected by the primary cutaneous lymphoma.

Primary Rosai-Dorfman disease of the central nervous system: A clinical, histological, and molecular appraisal.

Rosai-Dorfman disease (RDD) is characterized by clonal proliferation of S-100 positive histiocytes and variable emperipolesis. It commonly affects cervical lymph nodes. Central nervous system (CNS) involvement is extremely rare. We attempted to evaluate the Cyclin D1 expression and frequency of KRAS and BRAF mutations in the RDD involving the CNS. All patients with histopathologically diagnosed RDD involving CNS were recruited from 2011 to 2022. All cases were subjected to immunohistochemistry for CD68, CD163, S100, CD1a, GFAP, CD207, EMA, ALK, BRAFV600E, IgG4, IgG, and CyclinD1. The real-time polymerase chain reaction (RT-PCR) for hotspot mutation analysis of KRAS (exons 2, 3, and 4) and BRAF (V600E) was conducted on formalin-fixed paraffin-embedded tissue using a commercial kit (EntroGen). A total of seven cases were included. The median age was 31 years, with six men and one woman. It showed spinal cord (n = 4) and intracranial (n = 3) involvement. Histologically, all cases showed histiocyte-rich inflammation with evidence of emperipolesis. These histiocytes were positive for S100, CD68, CD163, and Cyclin D1, whereas negative for CD1a, CD207, and EMA. BRAF V600E was expressed in a single case. None of the control cases (demyelination and infarction) with histiocytic infiltrate showed Cyclin D1 expression. Four RDD cases showed increased IgG4-positive plasma cells (>10/HPF) and IgG4/IgG ratio (>40%). BRAF V600E mutation was detected in one case (14.28%), while none showed KRAS mutation. RDD involving CNS is extremely rare and diagnostically challenging. Nuclear Cyclin D1 expression along with S-100 positivity in the tumor cells is a strong diagnostic clue. BRAF and KRAS mutations are rare in CNS RDD.

Extranodal Rosai-Dorfman Disease: a rare presentation involving anterior chest wall in a middle-aged female.

Rosai-Dorfman Disease is a rare benign disorder involving overproduction of immune cells, causing swollen lymph nodes and, in rare cases, the sternum. The sternal involvement may cause chest pain and masses. Diagnosis is confirmed through clinical examination, biopsy, and imaging. Treatment options may include surgery, radiation, or steroids. In this case study, we present an unusual example of extranodal Rosai-Dorfman Disease involving the sternum, bilateral clavicles and first three ribs, and pectoral muscle with no associated lymphadenopathy or systemic symptoms in a 57-year-old female. The etiology, pathology, immunohistochemistry, imaging findings, and treatment options of this unique disease are discussed.

Emperipolesis in pleural fluid mesothelial cells. A phenomenon not associated with Rosai-Dorfman disease, report of a case.

Emperipolesis is a cell-within-cell phenomenon distinct from phagocytosis more often described in Rosai-Dorfman disease, where usually lymphocytes or other bone marrow cells (plasma cells, erythroblasts or neutrophils) are entirely surrounded but not engulfed by macrophages as the host cell, but occasionally megakaryocytes and neoplastic could be. Mesothelial cell has been described in a couple of cases of lymphomas affecting serous membranes, but never described in pleuritis. In the present work, the first case of emperipolesis by mesothelial cells in a patient with self-limited pleural effusion was demonstrated by immunohistochemistry and Electron Microscopy studies.

A rare presentation of Rosai-Dorfman-Destombes disease with central nervous system involvement and cutaneous wounds.

OBJECTIVE: The aim of this case report is to investigate an uncommon presentation of Rosai-Dorfman-Destombes (RDD) disease, and discuss possible differential diagnoses and treatment options for this pathology. RDD is a rare disorder of histiocytes that typically presents in patients as painless cervical lymphadenopathy. However, this case involves a patient with the central nervous system (CNS) type of RDD who later developed cutaneous lesions. METHOD: Several differential diagnoses were examined, including hidradenitis suppurativa, pilonidal cyst and pressure ulcers. It is important to be able to exclude these diagnoses based on the presentation, patient demographic and wound location. RESULTS: Biopsies verified the presence of RDD in the patient's suprasellar hypothalamic mass and skin lesions, confirming the patient had both CNS-RDD and cutaneous-RDD in the absence of lymphadenopathy. CONCLUSION: Recognising the unique manifestations of rare diseases such as RDD prevents delay of proper intervention and treatment.

Unifocal Type-3 Mixed Histiocytosis in a 10-Years Old Child.

BACKGROUND: Histiocytoses patients present with highly heterogeneous clinical and histopathological pictures requiring multidisciplinary management. Mixed histiocytosis is a recently described group of syndromes defined by the histological overlap of Langerhans cell histiocytosis and other histiocytic proliferations that include three clinically and prognostically different conditions (i.e., Type-1-3 mixed histiocytosis). CASE REPORT: We describe a 10 year-old boy with unifocal (type-3) mixed histiocytosis - Langerhans cell histiocytosis combined with a lesion with features intermediate between Rosai-Dorfman disease and reticulohistiocytosis. Sixty months after excision, the child is disease free. DISCUSSION: Cutaneous type-3 mixed histiocytosis (Langerhans cell histiocytosis with Rosai-Dorfman disease/reticulohistiocytosis) may occur in older childhood, be unifocal, and be cured by surgical excision.

Benign but fatal: management of endotracheal Rosai-Dorfman disease with acute onset.

Rosai-Dorfman disease (RDD) is a non-malignant condition mainly manifesting as a proliferation of histiocytes in lymph nodes. Endotracheal RDD (ERDD) with an acute onset presentation is extremely rare. There are few case reports of ERDD mainly concerning its pathology, diagnostics and bronchoscopic treatment, without providing sufficient clinical information from a comprehensive perspective. As a novel and challenging technique, tracheal resection and reconstruction (TRR) with spontaneous-ventilation video-assisted thoracoscopic surgery (SV-VATS) has been reported as feasible and safe in highly selected patients, but few centres have shared their experience with this approach. This case-based discussion includes not only practical issues in the management of a life-threatening ERDD patient, but also specialists' views on the management of acute obstructive airway, and the surgeons' reflection on TRR with SV-VATS.

PU.1 is a useful nuclear marker to distinguish between histiocytosis and histiocyte-rich tumours.

AIMS: The aim was to test the expression of PU.1 on different types of histiocytoses and to test the utility of PU.1 in confirming or excluding a histiocytic origin in tumour samples with suspicion of histiocytosis. METHODS AND RESULTS: We analysed 66 biopsies of nonmalignant histiocytoses represented by Langerhans-cell histiocytosis (n = 13), Erdheim-Chester disease (ECD) (n = 19), Rosai-Dorfman disease (RDD) (n = 14), mixed ECD-RDD (n = 3), ALK-positive histiocytosis (n = 6), and juvenile xanthogranuloma (n = 11). All cases were positive for PU.1 in reactive and neoplastic histiocytes. In addition, 39 cases of tumours with high-grade cytological atypia were referred to our center as suspicion of malignant histiocytosis/histiocytic sarcoma and only 18 were confirmed. Indeed, more than half of these tumours (21/39) were either undifferentiated malignant tumours with a stroma rich in histiocytes, diffuse large B-cell lymphoma, or high-grade dedifferentiated liposarcoma. PU.1 was useful to distinguish between the negativity of large atypical nuclei and the positivity of stromal reactive histiocytes. CONCLUSION: PU.1 is expressed by all types of histiocytosis. It distinguishes histiocytosis from histiocyte-rich tumours with an easy interpretation due to its sharp nuclear staining. Its negativity in lesional/tumour cells in histiocyte-like lesions is useful to eliminate a histiocytosis.

Characterizing Rosai-Dorfman disease with [18F]FDG PET/CT: a retrospective analysis of a single-center study.

OBJECTIVES: Rosai-Dorfman disease (RDD) is a rare non-Langerhans cell histiocytic proliferative disorder. We performed a retrospective study to characterize the clinical and [18F]FDG PET/CT features of RDD. METHODS: We retrospectively recruited 38 RDD patients with [18F]FDG PET/CT scan in our center. [18F]FDG PET/CT features were assessed, and clinical and follow-up data were recorded. RESULTS: In the recruited patients, 20/38 (52.6%) patients had single-system disease, while others (18/38, 47.4%) had disease affecting multiple system. RDD most commonly involved the upper respiratory tract (47.4%), followed by cutaneous/subcutaneous lesion (39.5%), lymph node (36.8%), bone (31.6%), central nervous system (28.9%), and cardiovascular system (13.2%) in the recruited patients. In PET/CT, the RDD lesions were FDG-avid, and the SUVmax of the hottest lesion in an individual patient was positively correlated with C-reactive protein levels (r = 0.418, p = 0.014), and negatively correlated with hemoglobin levels (r = -0.359, p = 0.036). The overall response rate of the first-line treatment was 80.8% in newly diagnosed RDD patients, and for patients with relapsed/progressive RDD, the overall response rate was 72.7%. CONCLUSION: [18F]FDG PET/CT could be a useful tool for evaluating RDD. KEY POINTS: • About half of the patients with Rosai-Dorfman disease had single-system disease, while others had disease affecting multiple system. Rosai-Dorfman disease most commonly involved the upper respiratory tract, followed by cutaneous/subcutaneous lesion, lymph node, bone, central nervous system, and cardiovascular system. • In [18F]FDG PET/CT, Rosai-Dorfman disease was usually hypermetabolic, and the SUVmax of the hottest lesion in an individual patient was positively correlated with C-reactive protein levels. • Rosai-Dorfman disease usually has a high overall response rate after treatment.

Comparison of neuroimaging features of histiocytic neoplasms with central nervous system involvement: a retrospective study of 121 adult patients.

OBJECTIVES: To compare neuroimaging characteristics of three types of histiocytoses, namely Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD), with central nervous system (CNS) involvement. METHODS: A total of 121 adult patients with histiocytoses (77 LCH, 37 ECD, and 7 RDD) and CNS involvement were retrospectively included. Histiocytoses were diagnosed based on histopathological findings combined with suggestive clinical and imaging features. Brain and dedicated pituitary MRIs were systematically analyzed for tumorous, vascular, degenerative lesions, sinus, and orbital involvement and for hypothalamic pituitary axis involvement. RESULTS: Endocrine disorders, including diabetes insipidus and central hypogonadism, were more common in LCH patients than in ECD and RDD patients (p < 0.001). In LCH, tumorous lesions were mostly solitary (85.7%), located in the hypothalamic pituitary region (92.9%), and without peritumoral edema (92.9%), while in ECD and RDD, tumorous lesions were often multiple (ECD: 81.3%, RDD: 85.7%), their distribution was more widespread with meninges mostly involved (ECD: 75%, RDD: 71.4%), and they most likely presented with peritumoral edema (ECD: 50%, RDD: 57.1%; all p ≤ 0.020). Vascular involvement was an exclusive imaging characteristic of ECD (17.2%), which was not observed in LCH or RDD; this was also associated with a higher risk of death (p = 0.013, hazard ratio = 11.09). CONCLUSION: The typical characteristic of adult CNS-LCH was endocrine disorders with radiological findings limited to the hypothalamic pituitary axis. The pattern of multiple tumorous lesions with predominant involvement of meninges was the main manifestation of CNS-ECD and CNS-RDD, while vascular involvement was pathognomonic for ECD and associated with poor prognosis. CLINICAL RELEVANCE STATEMENT: Involvement of the hypothalamic-pituitary axis is the typical imaging characteristic of Langerhans cell histiocytosis. Multiple tumorous lesions, predominantly involving but not limited to meninges, occur in most Erdheim-Chester disease and Rosai-Dorfman disease patients. Vascular involvement occurs only in Erdheim-Chester disease patients. KEY POINTS: • The different distribution patterns of brain tumorous lesions can help differentiate among LCH, ECD, and RDD. • Vascular involvement was an exclusive imaging finding of ECD and was associated with high mortality. • Some cases with atypical imaging manifestations were reported to further expand the knowledge on these diseases.

The clinical importance of the host anti-tumour reaction patterns in regional tumour draining lymph nodes in patients with locally advanced resectable gastric cancer: a systematic review and meta-analysis.

BACKGROUND: The status of regional tumour draining lymph nodes (LN) is crucial for prognostic evaluation in gastric cancer (GaC) patients. Changes in lymph node microarchitecture, such as follicular hyperplasia (FH), sinus histiocytosis (SH), or paracortical hyperplasia (PH), may be triggered by the anti-tumour immune response. However, the prognostic value of these changes in GaC patients is unclear. METHODS: A systematic search in multiple databases was conducted to identify studies on the prognostic value of microarchitecture changes in regional tumour-negative and tumour-positive LNs measured on histopathological slides. Since the number of GaC publications was very limited, the search was subsequently expanded to include junctional and oesophageal cancer (OeC). RESULTS: A total of 28 articles (17 gastric cancer, 11 oesophageal cancer) met the inclusion criteria, analyzing 26,503 lymph nodes from 3711 GaC and 1912 OeC patients. The studies described eight different types of lymph node microarchitecture changes, categorized into three patterns: hyperplasia (SH, FH, PH), cell-specific infiltration (dendritic cells, T cells, neutrophils, macrophages), and differential gene expression. Meta-analysis of five GaC studies showed a positive association between SH in tumour-negative lymph nodes and better 5-year overall survival. Pooled risk ratios for all LNs showed increased 5-year overall survival for the presence of SH and PH. CONCLUSIONS: This systematic review suggests that sinus histiocytosis and paracortical hyperplasia in regional tumour-negative lymph nodes may provide additional prognostic information for gastric and oesophageal cancer patients. Further studies are needed to better understand the lymph node reaction patterns and explore their impact of chemotherapy treatment and immunotherapy efficacy.

Neurological Manifestations of Histiocytic Disorders.

PURPOSE OF REVIEW: Histiocytic disorders, including Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD), are rare neoplasms that may present with a spectrum of neurologic involvement. Diagnostic delay is common due to heterogeneity in presentation and challenging pathology. RECENT FINDINGS: Recent advances in the treatment of these diseases targeted towards mutations in the MAP kinase pathway have led to an improved prognosis in these patients with neurologic involvement. It is critical for clinicians to have a high index of suspicion to allow for early targeted treatment and optimize neurologic outcomes. A systematic approach to diagnosis is presented in this article to allow for accurate diagnosis of these rare diseases.

Histiocytoid melanoma: Diagnostic pitfall and mimicker of non-Langerhans cell histiocytoses including reticulohistiocytoma.

Melanoma and benign histiocytic proliferations can sometimes show considerable clinical and histopathologic overlap. Recently, cases of melanomas resembling xanthogranuloma and Rosai-Dorfman disease have been reported, and herein we report a case of melanoma closely mimicking reticulohistiocytoma. An 84-year-old man presented with a 1 cm purple-red nodule on his arm concerning for squamous cell carcinoma. While the biopsy findings resembled reticulohistiocytoma, the clinical context and regression changes at the lesion perimeter raised stronger concern for melanoma, which was confirmed with immunohistochemistry. We review prior rare reports of melanomas resembling non-Langerhans cell histiocytic proliferations and summarize helpful clinical and histopathologic clues to avoid a diagnostic pitfall when confronted with this unusual quandary.

Intracranial Rosai-Dorfman disease: a case report and review of the literature.

RDD involving the central nervous system is rarely reported. To better understand the disease and explore the treatments, we reported this case and review the literature.

A unique case of isolated thoracic spinal Rosai-Dorfman disease related to IgG4.

Rosai-Dorfman disease (RDD) is a rare benign histiocytosis usually characterized by massive cervical lymphadenopathy and systemic manifestations. Extranodal, especially spinal involvement, is extremely rare. Our case was deemed worthy of presentation because it was the first reported isolated case of spinal RDD related to IgG4 and mimicked meningioma clinically and radiologically. A case with an intradural extramedullary mass causing neurological compression findings in the thoracic spinal region and radiologically mimicking meningioma is presented. In the histomorphological examination of the resection material, polymorphonuclear leukocytes in the dura, histiocytes showing emperipolesis, an increase in collagenized fibrous connective tissue, and intense lymphoplasmacytic cell infiltration accompanied by obliterative phlebitis were observed. Immunohistochemically, the histiocytic cells were found to be S-100 protein, CD68, and CD163 positive and CD1a and langerin negative, and more than half of the plasma cells were immunoglobulin-G4 (IgG4) positive. Although rare, RDD or IgG4-related meningeal disease should be considered in the differential diagnosis of dural-based spinal masses that radiologically suggest meningioma. The pathologist should be aware that these two histopathological entities may coexist. To our knowledge, this is the first case of "isolated spinal RDD related to IgG4" reported in the literature.

The changing landscape of pediatric histiocytoses: Birth, life, and transdifferentiation of pediatric histiocytes.

Histiocytic neoplasms in the children are very rare, and histiocytoses can occur in the perinatal period. The presumed origins and presentation of specific histiocytoses in the pediatric age group are described. Common and newly described histiocytoses are presented including Langerhans cell histiocytosis, Rosai-Dorfman disease, histiocytic sarcoma, ALK positive histiocytosis, and hemophagocytic lymphohistiocytosis. Molecular findings common to pediatric histiocytoses are also discussed.