Histiocytic Disorder Research Articles

A rare presentation of isolated intraosseous Rosai-Dorfman disease of the tibia – The role of whole-body magnetic resonance imaging in management

Rosai–Dorfman disease (RDD) is a rare non-Langerhans histiocytic disorder, usually presenting with enlarged cervical lymph nodes. Extranodal involvement is quite common and synchronously involves the nasal cavity, paranasal sinuses, skin, orbit, central nervous system, and rarely bones. Isolated bone involvement is rare and can present with local symptoms such as pain, swelling, restriction of activity, and occasionally pathological fracture. The most common sites of osseous RDD are the cranium, facial bones, and tibia, in decreasing order of frequency. Imaging findings of primary osseous RDD can be variable and there are no key features to diagnose this entity with certainty. Hence, the primary role of imaging is to plan the management and post-treatment follow-up. Here, we present a case of primary osseous RDD involving tibial diaphysis and emphasize the importance of whole-body magnetic resonance imaging in ruling out systemic involvement.

A case of indeterminate cell histiocytosis with ETV3-NCOA2 translocation.

Indeterminate cell histiocytosis (ICH) is a rare histiocytic disorder characterized by a proliferation of CD1a+ and CD207/langerin- cells. Recent molecular analyses have identified ETV3-NCOA2 translocation as a possible aetiopathogenesis of ICH. Herein, we describe the first Japanese case of ICH with ETV3-NCOA2 translocation. A 79-year-old Japanese man presented with a 1-year history of pruritic erythematous papules and nodules on his trunk and extremities. Histological examination revealed a dense and diffuse sheets-like infiltration of medium-sized histiocyte-like cells from the epidermis to the deep dermis. Immunohistochemically, the atypical cells were positive for CD1a but negative for CD207/langerin. Fluorescence insitu hybridization using NCOA2 break-apart probes confirmed a chromosomal break occurring on NCOA2 monoallele in the tumor cells. Furthermore, ETV3 exon 4-NCOA2 exon 14 translocation was identified in formalin-fixed paraffin-embedded skin samples using reverse transcription polymerase chain reaction and subsequent direct DNA sequencing. He also presented with interspersed eczematous plaques on his trunk and reactive dermatopathic lymphoadenopathy without any infiltration of ICH. He was treated with topical corticosteroids and narrowband UVB phototherapy. Four months later, his ICH skin eruptions, eczematous plaques, and lymphoadenopathy gradually regressed. Our case supports the notion that the detection of ETV3-NCOA2 translocation can be useful for diagnosis of ICH.

ALK-Positive Histiocytosis and its Distinctive Manifestation in the Breast

Abstract Introduction/Objective ALK-positive histiocytosis (APH) is a rare histiocytic proliferation disease that harbors ALK rearrangements, often involving fusion with KIF5B. Primary cases in the unilateral breast are exceptionally uncommon, with only a few reported cases globally, characterizing it as a unique histiocytic proliferation disorder. Methods/Case Report In our study, we report a case of unilateral multifocal breast involvement of ALK-positive histiocytosis following bilateral breast core biopsies in a 56-year-old Hispanic woman who presented with bilateral breast masses. Right breast imaging demonstrated multiple nodular densities, further characterized on ultrasound as a hypoechoic region of 8 cm with increased vascularity. On right breast biopsy, prominent proliferation of histiocytes (lacking high-grade cytologic atypia) with chronic inflammation, few giant cells, and focal cholesterol clefts were identified. On immunohistochemical studies, the lesional cells were variably positive for histiocytic markers CD68, CD163, and PU.1 and were negative for S100 and pancytokeratin. ALK1 showed multifocal staining in the lesional cells as confirmed on repeat study; however, ALK (D5F3), GMS and acid fast studies were negative. The presence of focal cholesterol clefts, scattered giant cells, and chronic inflammation lead us to consider aberrant ALK expression in a reactive process. However, APH was definitively diagnosed through confirmation of clonal histiocyte proliferation, observed findings on morphology, immunophenotyping, and the presence of KIF5B-ALK gene fusion as detected by comprehensive solid tumor fusion panel testing. Results (if a Case Study enter NA) NA Conclusion It is noteworthy that ALK-positive histiocytosis can occasionally present alongside features of a reactive process in the breast. Therefore, considering any history of prior surgery or trauma at the lesion site is crucial. However, we recommend a comprehensive approach in most cases, which includes morphological, immunohistochemical, and molecular analysis on all suspected histiocytosis cases. This approach aims to increase awareness and detection of this rarely described entity and to precisely distinguish it from other diseases for prognostic and therapeutic purposes.

Rare Case of Cutaneous Rosai Dorfman Disease Involving the Nail

Abstract Introduction/Objective Rosia-Dorfman Disease (RDD) is a rare benign non-Langerhans cell histiocytic disorder of unknown etiology with heterogeneous clinical features. RDD was first described by Destombes in 1965 under the term “adenitis with lipid excess.” However, it is named after Rosai and Dorfman, who characterized the further histopathological features of the disease in 1969. The characteristic presentation of RDD is lymphadenopathy, and extra nodal sites include bone, upper respiratory tract, central nervous system, retroperitoneum, and skin. The management of RDD depends on the site of involvement and the presence or absence of the symptoms. Multifocal and refractory diseases require systemic treatment. Surgical resection can be considered in symptomatic and resect- able diseases. Methods/Case Report A 16-year-old Asian female with no significant past medical history presented with a painful verrucous lesion on the left 5th finger for one year with bleeding and purulent discharge. Excision was performed, and histologically, there was extensive infiltration of large histocytes in the dermis with occasional lymphocytes and plasma cells. The histiocytes were engulfing the intact inflammatory cells, exhibiting the emperipolesis phenomenon. Immunohistochemically, S100 and CD68 were positive in the large histiocytes, and leukocyte common antigen (LCA) was positive in the background lymphocytes. Based on histology and immunohistochemistry, RDD diagnosis was rendered. Results (if a Case Study enter NA) N/A Conclusion RDD is a rare condition that poses challenges in diagnosis and management. The key diagnostic factors are histological features and immunohistochemistry to exclude other pathological disorders. Treatment should be tailored according to the needs of each patient and as required to optimize the outcome. We recommend an appropriate diagnosis of this entity in a timely manner to prevent any further long-term complications.

Unexpected Presentations of Histiocytic Disorders as Mass Lesions in the Central Nervous System and Spine

Abstract Introduction/Objective A number of neoplastic and non-neoplastic hematolymphoid lesions can involve the CNS and spine. The majority are lymphomas, but some are rare lesions that mimic primary neoplasms clinically, radiologically, and even pathologically. Here, we present our experience of such cases. Methods/Case Report Pathology archives were searched, and five cases representing different challenges were identified to review clinical, radiological, and pathologic features. Case 1. 31-year-old female presented with vision changes and hearing loss and numerous supratentorial extra-axial masses, suspicious for meningiomatosis. Extensive lymphoplasmacytic infiltrate was seen at Intraoperative consult (IOC). Final diagnosis was Rosai-Dorfman disease with features of IgG4 related disease. Case 2. 31-year-old female with Chronic myeloid leukemia (CML), which progressed to AML presented with a right frontal brain mass. IOC displayed atypical hematolymphoid infiltrate. Final diagnosis was myeloid sarcoma. Case 3. 29-year-old male presented with a T10 vertebral lesion. IOC showed hypercellular tissue with atypia and was deferred. Subsequently, histiocytic sarcoma was diagnosed. Case 4. 22-year- old male presented with a T3-T4 intradural, extramedullary mass radiologically thought to be a meningioma. No IOC was requested. Final diagnosis was juvenile xanthogranuloma. Case 5. 36-year-old male presented with a C7-T1 dura-based mass. IOC revealed granulomatous inflammation, eventually resulting in a diagnosis of non-necrotizing granulomatous inflammation, suggesting sarcoidosis. Results (if a Case Study enter NA) NA Conclusion These cases highlight the importance of incorporating all clinical and radiological findings into pathologic evaluation, while being alert for mimickers and pitfalls. Both practicing general surgical pathologists and neuropathologists should remain alert to such unexpected and unusual cases especially at the time of IOC and initiate appropriate work-up with expedited diagnostic protocols such as intraoperative cultures, flow cytometry, and cytogenetics, as the differential diagnosis is broad with inflammatory, infectious, and neoplastic possibilities, presenting a variety of challenges.

7292 Central AVP Deficiency in Erdheim-Chester Disease in the Era of Molecular Diagnostics

Abstract Disclosure: J. Hewlett: None. S. Mohan: None. C.J. Davidge-Pitts: None. J. Abeykoon: None. R. Go: None. D.Z. Erickson: None. Objective: Erdheim-Chester Disease (ECD) is a multisystem histiocytic disorder which can infiltrate the pituitary gland, often leading to endocrine dysfunction. Central Arginine Vasopressin Deficiency (cAVP-D) commonly affects ECD patients, and those harboring BRAFV600E are reported to have an increased risk. Insufficient data exist about the risk associated with other mutations, and if cAVP-D or pituitary imaging improves with targeted therapies (TT). Methods: We conducted a review of a prospectively maintained database of adults with ECD treated at a tertiary center between 1992-2023. Objectives of this study were to identify mutations associated with cAVP-D and assess for improvement in cAVP-D (remission of disease or decrease in dose of desmopressin) or pituitary gland involvement (via MRI imaging) following TT for ECD. Results: Of 148 patients with ECD, the majority were male (98, 66.2%) and the mean age at diagnosis was 56.5 years [range: 19-82]. Median length of follow-up was 24 months (95% CI, 17 to 27). Of 121 (81.8%) patients with molecular testing results, 89 (73.6%) harbored a somatic mutation. 67 of 89 (75.3%) carried BRAF mutations, with BRAFV600E in 61 (91.0%) and missense mutations/fusions in 6 (9.0%). 22 of 89 (24.7%) patients harbored other somatic mutations, with MAP2K1 in 13 (14.6%) being the most common. 35 (23.6%) patients were diagnosed with cAVP-D, and the median onset of polyuria and polydipsia prior to diagnosis of ECD was 51 months (95% CI, -120 to -6). Molecular testing was performed in 28 patients with cAVP-D: 17 (60.7%) harbored BRAF mutation and 3 (10.7%) MAP2K1 mutation. There was no significant association between the presence of cAVP-D and MAP2K1 (p=0.69, 95% CI, -0.08 to 0.21). The association between cAVP-D and BRAF did not reach statistical significance (p=0.07, 95%CI, -0.03 to 0.38). Additionally, there was no association between BRAF and timing of cAVP-D symptoms before ECD diagnosis (p=0.08, 95% CI -163.4 to 10.3). Pituitary MRI was available in 32 patients with cAVP-D (91.4%) showing infundibular involvement in 17 (53.1%) and loss of the posterior bright spot in 5 (15.6%). 28 (80%) patients with cAVP-D received systemic therapy, 18 (64.3%) of whom received TT. One patient with cAVP-D was able to discontinue desmopressin. Improvement of pituitary MRI was noted in 7 (21.9%), among whom 4 received TT, 2 received systemic non-TT, and 1 was lost to follow-up. There was no significant MRI improvement associated with TT (p=0.67, 95% CI -0.30 to 0.42). Conclusion: In this large cohort of patients with ECD, of whom the majority underwent molecular testing, we identified no association between MAP2K1 mutation and cAVP-D, and no impact of TT on the clinical course or MRI findings associated with cAVP-D. BRAF mutation carriers were more likely to have cAVP-D and more likely to have onset of symptoms closer to ECD diagnosis, but the results did not reach statistical significance. Presentation: 6/2/2024

Erdheim–Chester disease: An elusive diagnosis in a 50‐year‐old Ethiopian man presenting with diffuse sclerotic bone lesion

Key Clinical MessageDiagnosis of Erdheim–Chester disease (ECD) requires the clinician to be familiar with its various manifestations, classic radiologic and histologic features. This case highlights the significance of considering ECD in any patient presenting with bone pain and symmetric osteosclerosis of long bones of extremities to allow for early diagnosis and treatment.AbstractErdheim–Chester disease (ECD) is a rare non‐Langerhans histiocytic disorder with diverse clinical manifestations, ranging from indolent, localized presentation to life‐threatening, multi‐systemic disease. Delayed or erroneous diagnosis is common. The presence of classic radiographic finding along with foamy histiocytes that is positive for CD68 but negative for CD1a on histologic examination establishes the diagnosis. We report a second case of ECD from Ethiopia. A 50‐year‐old Ethiopian man presented with a 13‐year history of bilateral lower leg bone pain, cold intolerance, somnolence, constipation, impotence, decreased libido, and secondary infertility. The diagnosis was suspected when skeletal X‐ray revealed bilateral symmetric sclerosis of metadiaphysis of femur, tibia, and humerus. The demonstration of foamy histiocytes that were positive for CD68 but negative for CD1a on histologic examination with immunohistochemical staining confirmed the diagnosis. Evaluation for the extent of the disease revealed coated aorta sign, hairy kidney sign, and cystic lesion with ground glass opacity of lung, primary hypothyroidism, and hypergonadotropic hypogonadism. ECD is rare histiocytic neoplasm with wide range of clinical features which often delay the diagnosis. Clinician should be mindful of the various presentations and the classic radiographic and histologic features of ECD. This case highlights the significance of entertaining ECD in any patient presenting with lower leg bone pain and symmetric osteosclerosis of long bones of lower extremities to allow for early diagnosis and treatment.

Current State of Targeted Therapy in Adult Langerhans Cell Histiocytosis and Erdheim-Chester Disease.

The mitogen-activated protein kinase (MAPK) pathway is a key driver in many histiocytic disorders, including Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD). This has led to successful and promising treatment with targeted therapies, including BRAF inhibitors and MEK inhibitors. Additional novel inhibitors have also demonstrated encouraging results. Nevertheless, there are several problems concerning targeted therapy that need to be addressed. These include, among others, incomplete responsiveness and the emergence of resistance to BRAF inhibition as observed in other BRAF-mutant malignancies. Drug resistance and relapse after treatment interruption remain problems with current targeted therapies. Targeted therapy does not seem to eradicate the mutated clone, leading to inevitable relapes, which is a huge challenge for the future. More fundamental research and clinical trials are needed to address these issues and to develop improved targeted therapies that can overcome resistance and achieve long-lasting remissions.

Erdheim-Chester Disease Masquerading as CLIPPERS.

To present 4 patients with Erdheim-Chester disease (ECD) based on clinical, radiologic, histopathologic, and molecular genetic findings who had enhancing brainstem lesions and were initially believed to have chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Case series. Although patients with ECD can demonstrate clinical and imaging features similar to CLIPPERS, refractoriness to corticosteroids, lack of fulfillment of specific MRI criteria (i.e., enhancing lesions >3 mm, T2 abnormalities that exceed areas of T1 postgadolinium enhancement), and systemic findings such as "hairy kidney" appearance and metadiaphyseal osteosclerosis on 18F-fluorodeoxyglucose PET-CT help discriminate it from CLIPPERS. ECD is a histiocytic neoplasm characterized by multiorgan infiltration of clonal histiocytes carrying activating variants of the MAPK-ERK pathway. Neurologic involvement occurs in up to 40% of ECD with frequent brainstem lesions that can mimic acquired neuroinflammatory disorders, such as CLIPPERS. ECD is an important CLIPPERS mimic with distinct pathophysiology and targeted treatments. We highlight the need to consider histiocytic disorders among other alternate diagnoses when findings are not classic for CLIPPERS.

Palbociclib in Solid Tumor Patients With Genomic Alterations in the cyclinD-cdk4/6-INK4a-Rb Pathway: Results From National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice Trial Arm I (APEC1621I).

The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice trial assigned patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with tumors that harbored prespecified genomic alterations in the cyclinD-CDK4/6-INK4a-Rb pathway with intact Rb expression were assigned and treated with the cdk4/6 inhibitor palbociclib. Patients received palbociclib orally once daily for 21 days of 28-day cycles until disease progression, intolerable toxicity, or up to 2 years. The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival. Twenty-three patients (median age, 15 years; range, 8-21) were enrolled; 20 received protocol therapy and were evaluable for toxicity and response. Of the evaluable patients, the most common diagnoses were osteosarcoma (n = 9) and rhabdomyosarcoma (n = 6). A single actionable gene amplification was found in 19 tumors (CDK4, n = 11, CDK6, n = 2, CCND3, n = 6), with one tumor harboring two amplifications (CDK4 and CCND2). Hematologic toxicities were the most common treatment-related events. No objective responses were seen. Two patients with tumors harboring CDK4 amplifications (neuroblastoma and sarcoma) had best response of stable disease for six and three cycles. Six-month progression was 10% (95% CI, 1.7 to 27.2). The CDK4/6 inhibitor palbociclib at 75 mg/m2 orally daily was tolerable in this heavily pretreated cohort. No objective responses were observed in this histology-agnostic biomarker-selected population with treatment-refractory solid tumors, demonstrating that pathway alteration alone is insufficient in pediatric cancers to generate a response to palbociclib monotherapy.

Erdheim-chester disease with bilateral proptosis, coated aorta and hairy kidney

Erdheim-Chester disease (ECD) is a rare histiocytic disorder with a spectrum of clinical manifestations, ranging from asymptomatic single-organ involvement to multisystem disease. We present a classic case of ECD with detailed radiographic and histopathologic findings. A 63-year-old Thai female with a history of triple vessel disease post-PCI presented with bilateral proptosis and blurred vision for one year. On admission, she exhibited marked proptosis epiblepharon, lagophthalmos, conjunctival injection, chemosis, limited extraocular movement and cranial nerve II palsy. Imaging showed increased bilateral retro-orbital infiltrative lesions, osteosclerotic changes, and soft tissue thickening along the great vessels and retroperitoneum. A retro-orbital soft tissue biopsy showed foamy histiocytic proliferation with Touton giant cells. EDC was confirmed by next-generation sequencing revealing a BRAF V600E mutation. This patient received pegylated interferon-alpha. At 1-year follow-up visit, the disease remained stable. In this report, we present a classic case of EDC. The rarity of this disease makes it challenging to diagnose. The typical presentation characteristics raise awareness for the diagnosis of EDC, which is based on features such as osteosclerotic lesions in the long bones, soft tissue infiltration in medium to large vessels (coated aorta) and the bilateral pelvicalyceal systems (hairy kidney). These findings were confirmed through tissue pathology and molecular diagnostics.

Multiple foci of Rosai–Dorfman disease in colon: a case report

BackgroundRosai–Dorfman disease (RDD) is an uncommon proliferative histiocytic disorder involving lymph nodes and various organs. Forty-three percent of RDD cases originate from extranodal sites; however, RDD rarely arises from the colon.Case presentationA 75-year-old man was admitted to our hospital because of intra-abdominal masses that were incidentally detected during surveillance by computed tomography (CT) after treatment for lung cancer. Enhanced CT showed two mass lesions located in the cecum to the appendix (diameter, 40 mm) and around the sigmoid colon (diameter, 24 mm). Positron emission tomography (PET)-CT revealed an apparent uptake of fluorodeoxyglucose. Intraluminal endoscopy did not reveal definite mucosal abnormalities. These findings suggest the presence of malignant neoplasms including gastrointestinal stromal tumors, lung cancer metastasis, and malignant lymphoma. Exploratory laparoscopy and/or tumor excision were planned to obtain a definitive diagnosis. Based on laparoscopic findings, ileocecal resection and sigmoidectomy were simultaneously performed to excise the tumors. Postoperative histopathological examination revealed multiple RDD originating from the mesocolon side of the cecum and the sigmoid colon. The patient did not receive any adjuvant therapy. No recurrence was observed one year after surgery.ConclusionRDD originating from the colon is extremely rare. Tumor extirpation or organ resection is sometimes required to obtain a definitive diagnosis of RDD, and minimally invasive surgery is helpful.

Lenalidomide and dexamethasone for Rosai-Dorfman disease: a single arm, single center, prospective phase 2 study

Rosai-Dorfman disease (RDD) is a rare heterogeneous histiocytic disorder lacking standardized first-line treatment. This single-center, phase 2 prospective study enrolled 13 newly diagnosed and 10 recurrent RDD patients from June 2021 to March 2023at Peking Union Medical College Hospital (Beijing, China). Lenalidomide 25mg days 1-21 plus dexamethasone 40mg days 1, 8, 15, 22 was administered in 28-day cycles, totaling 12 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR) to lenalidomide and dexamethasone (RD) regimen, toxicity, and overall survival (OS) measured from RD start to death or last follow-up. OS and PFS were estimated according to Kaplan-Meier survival analysis and compared with the log-rank test. For OS and OR rate, 95% confidence limits were obtained using the Clopper-Pearson method, with standard methods used for PFS. p<0.05 was considered statistically significant. The trial was registered with ClinicalTrials.gov (NCT04924647). The median age was 44 years (IQR 35-54). All patients had extranodal RDD. MAPK pathway alterations occurred in 6/18 (33%). Elevated IL-6 and TNF-α were found in 39% (n=9) and 70% (n=16), respectively. All patients received ≥6 cycles (median 12, range 6-12, IQR 10-12). The ORR was 87% (20/23, 95% CI 66%-97%), 30% (n=7) complete remission, 57% (n=13) partial remission). Treatment with RD significantly decreased median serum levels of both IL-6 (from 5.9 (IQR 4.2-8.7) to 2.9 (IQR 2.1-5.9) pg/mL, p=0.031) and TNF-α (from 12.2 (IQR 8.6-17.9) to 8.3 (IQR 6.1-10.5) pg/mL, p=0.0012). With a median 26 months follow-up (range 6-28, IQR 16-28), 4 patients relapsed and none died. Two-year OS and PFS were 100.0% (95% CI 85%-100%) and 69.0% (95% CI 51%-94%), respectively. No grade 3-4 adverse events or discontinuations due to adverse events occurred. Twelve patients (n=12, 52%) had grade 1-2 hematological toxicity. Other toxicities included constipation (n=2, 9%), glucose intolerance (n=2, 9%), edema (n=2, 9%), insomnia (n=1, 4%), and tremor (n=1, 4%). Lenalidomide and dexamethasone regimen is an effective and safe regimen for newly diagnosed and recurrent RDD. National Natural Science Foundation of China, Beijing Natural Science Haidian frontier Foundation Funding, and the National High Level Hospital Clinical Research Funding.

ETMR-31. A UNIQUE CASE OF CNS DIFFUSE, NON-SYSTEMIC ALK+ HISTIOCYTOSIS IN A PEDIATRIC PATIENT

Abstract BACKGROUND Histiocytic disorders are a group of rare diseases with accumulation of of macrophages, monocytes, or dendritic cells in various parts of the body. ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 that is very rarely described in pediatrics. METHODS A 20 month old male presented to an adult hospital after a prolonged period of headaches, vomiting, and loss of developmental milestones. Imaging demonstrated severe hydrocephalus and extensive thickened leptomeningeal enhacement with mass effect. He underwent VP shunt placement and revision, a T7-T10 laminectomy, and tumor debulking. Extensive molecular testing, including DNA and RNA analysis by NGS was performed and a CLTC::ALK fusion was identified, along with Tier III DNA variants, yielding a diagnosis consistent with ALK-Positive Histiocytosis, with diffusivity in the CNS system. Full evaluation demonstrated no involvement of the peripheral nervous system or other systemic involvement. He initially demonstrated signs of neuro-irritation, altered tone, and lower extremity clonus. RESULTS After review of very little literature published on similar patients, although none with a clinical picture matching his, he was started on a treatment course of high dose dexamethasone, vinblastine, and lorlatinib targeting the ALK+, likely driver, mutation of his disease. On evaluation scans two months into treatment, he showed no change in his disease burden. He was transitioned to clofarabine cycles with daily lorlatinib for continued targetted therapy. After six total cycles, he demonstrated a high partial to complete remission (allowing for evidence of scarred tissue) and tremendous neurologic and developmental milestone gains. CONCLUSIONS This case demonstrates a unique presentation in which there is little described in the literature in way of clinical features or treatment standards, and further none exactly similar to this patient. After undergoing extensive evaluation and therapy modication, he responded remarkably well and continues to have optimal quality of life.

Overview of histiocytic and dendritic disorders by the 5th version of WHO Classifi cation of Hematolymphoid Tumours from 2022.

Histiocytoses are rare disorders characterized by the accumulation of macrophages, dendritic cells, or monocyte-derived cells in various tissues and organs of children and adults, with a wide range of clinical manifestations, presentations, and histology. The histiocytoses are classified according to the WHO Classification, the last version of which was published in 2022, or according to the Histiocyte Society Classification, with the last version published in 2016. This text provides an overview of histiocytoses as described in the WHO Classification 2022.

Double Trouble: Co-occurrence of Langerhans Cell Histiocytosis and Rosai Dorfman Disease in a Toddler

The coexistence of Rosai-Dorfman disease (RDD) with Langerhans cell histiocytosis (LCH) is very rare, as to date only a handful of cases have been reported. Though both the entities come under the spectrum of histiocytic disorders, the patient outcomes are very different for each one of them. RDD is a benign disorder with often a self-limiting course; whereas LCH has a more aggressive outcome. The pathobiology of this rare co-occurrence is still unknown and the topic of several theories. Case presentation: We report a case of a 2-year-old female patient who presented with fever, pallor, lymphadenopathy and neck pain. X-ray radiograph and Computed Tomography (CT) scan chest showed multiple lytic lesions on vertebra. The biopsy finding of lymph node and bone marrow were consistent with a combined RDD-LCH disease. Conclusion: Combined RDD-LCH presentation is very rare and it’s pathophysiology is still elusive and a topic of numerous conjectures.

Case report: A rare case of isolated sigmoid Rosai-Dorfman disease on contrast-enhanced CT and 18F-FDG PET/CT

Rosai-Dorfman disease (RDD) is an uncommon histiocytic disorder that occurs in nodal and/or extranodal sites. Extranodal RDD exhibits a wide range of clinical and radiological presentations, frequently leading to misdiagnoses. Involvement of the gastrointestinal (GI) system is uncommon, accounting for less than 1% of the reported cases. Here we present a case of a 54-year-old male who complained of abdominal distention and was diagnosed with RDD affecting the sigmoid colon, manifesting as a sigmoid mass. The patient had a past medical history of liver transplantation due to hepatocellular carcinoma (HC). This report details the multiphase contrast-enhanced computed tomography (CT) and fluorodeoxyglucose (18F-FDG) positron emission tomography (PET-CT) imaging findings of RDD involving the sigmoid colon without lymphadenopathy, and a review of the relevant literature is provided.

Concurrent enhancer of Zeste homolog 2 (EZH2) over-expression with BRAFV600E mutation predicts a poor outcome in patients with Langerhans cell histiocytosis (LCH): A pilot study.

e18536 Background: Prior studies demonstrated upregulated EZH2 protein expression and p-ERK1/2 cascade signaling in histiocytic and dendritic cell neoplasms. BRAFV600E is the most common driver mutation reported in LCH patients (34-64%). In melanoma studies, a signaling pathway with BRAFV600E activating mutation resulted in upregulation of EZH2. The frequency of EZH2 co-expression with BRAFV600E is unknown in LCH. Given the limited durable responses after discontinuation of treatment with BRAF inhibitors in histiocytic disorders, we investigated the prognostic role of EZH2 overexpression and BRAFV600E mutation in LCH. Methods: We analyzed a cohort of 27 consecutive patients (pts) diagnosed with LCH at Moffitt Cancer Center and Tampa General Hospital between 2010-2022. Immunohistochemical (IHC) staining using antibodies against EZH2 (D2C9 clone, Cell Signaling) and BRAFV600E (VE1 clone, Ventana medical systems) were performed. Expression was assessed by an IHC score of stain intensity (0, 1+, 2+ and 3+) multiplied by percent positive cells (H score). H score ≥ 30 was considered as positive. Pyrosequencing was performed to detect BRAFV600E mutations and correlated with VE1 staining results. A positive outcome from either IHC or PCR was deemed indicative of mutation positivity, given the robust presence of mutation representation in melanoma studies through IHC. Results: Entire cohort were grouped for pts who had both EZH2 overexpression and BRAFV600E mutation (EZH2/BRAFV600E) versus those who did not. Out of 27 pts, 25.9% (n=7) had both EZH2/BRAFV600E. EZH2/BRAFV600E group differed from control group by age ( p=0.046). BRAFV600E mutation was identified in 37.03% (10) pts, and 40.7% (11) showed expression of VE1 by IHC study. Discrepancies between PCR and IHC study were observed in 4 pts and potentially attributable to the restricted availability of tissue samples. 63% and 48.1% of pts were positive for EZH2 and BRAFV600E respectively. 6 pts were observed, 8 underwent surgery with or without radiation, 12 received induction chemotherapy, and only 1 received a BRAF inhibitor. After 18.6 months of median follow up, 92.6% pts were alive. Overall response rate (ORR) to the 1st line therapy was 55.6%. In univariate analysis of OS, H score and BRAFV600E mutation trended towards worse OS but were not statistically significant owing to small sample size. However, BRAFV600E mutation and EZH2 over expression demonstrated a poor overall survival (OS) ( p=0.012). Conclusions: Our study indicates that concurrent presence of BRAFV600E mutation and EZH2 overexpression correlates with poor OS in LCH pts. We hypothesize that in a subset of LCH pts combination therapy targeting both EZH2 and BRAFV600E may improve ORR or overcome resistance to BRAF inhibitor monotherapy. However, the results of our pilot study need to be validated on a larger sample set.

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 etal. Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy. Br J Haematol 2024;205:127-137.

Clinical features and treatment outcomes of liver involvement in paediatric Langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children, and liver involvement in LCH is rare. This retrospective study reported the clinical features and prognosis of patients with hepatic LCH. Liver involvement was defined by histopathological findings, liver dysfunction or abnormalities, or ultrasound imaging. A total of 130 patients (14.5%) with hepatic LCH out of 899 in the LCH population were enrolled. Patients with liver involvement had greater frequencies of skin, lung, hearing system, and haematologic system involvement, and hemophagocytic lymphohistiocytosis (P<0.001, 0.001, 0.002, 0.009, and <0.001, respectively). Overall survival and progression-free survival were lower in LCH patients with liver involvement than in those without liver involvement (P<0.001 and <0.001). In patients with liver involvement, the overall survival (OS) and progression-free survival (PFS) rates were lower in patients with cholangitis than in those without cholangitis (P<0.020 and 0.030). For the treatment response, the response rate of hepatic LCH patients to initial first-line therapy (n=89) was 22.5%. However, there was no significant difference in the response rate or recurrence rate between patients who shifted from first-line treatment to second-line treatment (n=29) or to targeted therapy (n=13) (P=0.453 and 1.000). The response rate of hepatic LCH patients who received initial second-line therapy (n=13) was 38.5%. Two of these patients subsequently experienced bone recurrence. The response rate of hepatic LCH patients who received initial targeted therapy (n=16) was 75.0%. Three patients subsequently experienced recurrence, including 2 in the bone and 1 in the liver and skin. A total of 39.3% of patients who received second-line treatment had severe myelosuppression (grade III-IV), and 50.8% had varying degrees of gastrointestinal events, whereas there was no severe toxicity in patients who received first-line treatment and targeted therapy. Four patients underwent liver transplantation because of liver cirrhosis. The patients’ liver disease improved within a follow-up period of 18-79 months. This study demonstrated that LCH with liver involvement, especially cholangitis, indicates a poor prognosis. Targeted therapy provides a good treatment response and less toxicity. However, it may relapse after withdrawal. Liver transplantation is still a reliable salvage option for patients with end-stage liver disease.