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Background/aims: Ocular manifestations of histiocytosis and their genetic underpinnings are poorly characterised. This study characterises ocular sites of histiocytosis, notate genetic alterations and correlates to histiocytosis clinical features including subtype and sites of disease., Methods: Prospective registry-based study of predominantly adult histiocytosis patients at a single-institution tertiary referral centre. 180 eyes of 90 patients (46 males, 44 females) with histiocytosis (Erdheim-Chester disease 34, Rosai-Dorfman 20, xanthogranuloma 7, mixed histiocytosis 13, Langerhans cell histiocytosis (LCH) 15, ALK-positive histiocytosis 1). Ocular findings were categorised by the structure involved. Histiocytosis subtype, sites of disease and genetic status were correlated to ocular findings., Results: Ocular disease was present in more than half the histiocytosis patient cohort and occurred with other disease sites. Ocular findings were statistically significantly different across histiocytic subtypes with LCH subtypes having the lowest proportion of ocular findings (7%) and all other subtypes having rates of ocular findings which were five times that of patients with LCH (p=0.0009). Of patients with ocular findings, 41% of patients reported ocular symptoms and were significantly more in the group with ocular disease present versus those patients without ocular involvement. The presence of ocular findings was not statistically different by BRAF V600E, MAP2K1 or RAS isoform mutational status., Conclusions: Ocular disease is a common feature of histiocytosis with significant visual symptomatology and occurrence in tandem with multisystem sites. Ocular findings vary by histiocytic subtype. The mutational profile of the cohort reflects known mutations in this clinical population, with no specific driver mutation associated with ocular disease., Competing Interests: Competing interests: JHF-none, ASR-none, JC-none, RKR-consulting fees from Incyte, Celgene/MS, Blueprint, AbbVie, Promedior, CTI, Stemline, Galecto, Pharmaessentia, Protagonist, Constellation/Morphosys, Novartis, Sierra Oncology/GSK and Servier Research funding from Constellation Pharmaceuticals, Incyte, Zentalis and Stemline Therapeutics, DHA-none, ELD-unpaid editorial support from Pfizer and serves on an advisory board for Day One Biotherapeutics, Springworks Therapeutics and Opna Bio, all outside the submitted work., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Crystalloid storage histiocytosis (CSH) is a rare clinical condition characterized by abnormally high numbers of histiocytes with a large accumulation of crystalline immunoglobulins. Due to its relative rarity, clinical diagnosis of it is frequently incomplete or incorrect. We report a case with pulmonary crystal-storing histiocytosis that was mistakenly identified as lung carcinoma., Methods: Percutaneous lung biopsy, bronchoscopy., Results: Percutaneous lung biopsy pathology shows granulomatous inflammation with massive eosinophilic infiltration, immunohistochemistry shows CD68, kappa positive, S-100, desmin, myogenin, lambda negative. The final diagnosis is pulmonary crystal-storing histiocytosis., Conclusions: To get pathology tissue for a definitive diagnosis, patients with pulmonary nodules who have changes in tumor markers or nodule size should have bronchoscopy or percutaneous lung biopsy done as soon as possible.

SLC29A3 spectrum disorder, also known as histiocytosis-lymphadenopathy plus syndrome (HLPS), presents a wide variety of multi-systemic manifestations that can be mistaken for other conditions. Herein, we report a 9-year-old girl who presented with a complex clinical presentation since birth, including chronic generalized lymphadenopathy in association with hepatosplenomegaly, short stature, flexion contractures, hearing loss, hyperpigmentation, and heart anomalies. She was ultimately diagnosed with the SLC29A3 spectrum disorder., (© 2024 Wiley Periodicals LLC.)

H syndrome is a rare autosomal recessive genodermatosis that falls under the histiocytosis-lymphadenopathy plus syndrome. The term "H syndrome" includes manifestations such as hyperpigmentation, hypertrichosis, hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and occasionally hyperglycemia. The syndrome is associated with mutations in the SLC29A3 gene, which encodes the human equilibrative transporter 3 present in endosomes, lysosomes, and mitochondria. The generalized and ubiquitous presence of affected lysosomes and mitochondria contributes to the systemic and phenotypically heterogeneous manifestations of the syndrome. H syndrome manifestations are cutaneous, systemic, and organ-specific. The pathognomonic signs are hypertrichosis and hyperpigmentation in the inner thighs and shins. However, not all patients present with these symptoms. H syndrome management involves a multidisciplinary approach to address specific symptoms and complications. The prognosis of H syndrome depends on several factors, including the extent and severity of clinical manifestations, the presence of complications, and timely diagnosis and management. Further studies are needed to explore the association between prognosis and the different mutations encountered in H syndrome., (Copyright © 2024 Hematology/Oncology and Stem Cell Therapy.)

Purpose: Within the large umbrella of histiocytosis are a few similar yet heterogenous entities involving the orbit and periocular tissues with or without systemic infiltration, termed adult onset xanthogranuloma or orbital xanthogranuloma. Due to rarity of these conditions, different classifications in use, diverse clinical presentations and still unknown etiology, the aim of this paper was to provide an up-to-date literature review of the actual understanding of histiocytosis and its subgroups involving the orbit and periocular area, diagnostic strategies and therapeutic modalities., Methods: We present a review of literature and small case series comprising four patients diagnosed and treated in the period from 2001 until 2023 in our hospital. Clinical files of 4 patients with adult-onset xanthogranulomatous disease of the orbit and ocular adnexa (AOXGD) were reviewed retrospectively. Clinical, laboratory, radiological, histopathological, and immunohistochemical findings were reexamined., Results: Reviewing medical records of our patients with AOXGD, we found significant overlap between histiocytosis and different immune disorders. A broad workup should be considered in these patients as they can harbour severe immune disfunctions and hematologic disorders. Preferred treatment modality depends on a histopathologic type of AOXGD, clinical presentation and systemic involvement and should be conducted multidisciplinary., Conclusion: The diagnosis is often delayed because of its rarity and diverse clinical findings. Development of molecular genetic tests, detection of BRAF V600E mutation and different types of kinase mutations, mutations in transcriptional regulatory genes as well as tyrosine kinase receptors have shed a new light on the etiopathogenesis and potential targeted treatment of histiocytosis., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Purpose: Histiocytosis is one of the most challenging diseases in medical practice. Because of the broad spectrum of clinical manifestations, systemic involvements, unknown etiology, and complex management, different types of histiocytosis are still a big question mark for us. Orbital histiocytosis is characterized by the abnormal proliferation of histiocytes in orbital tissues. It could affect the orbit, eyelid, conjunctiva, and uveal tract. Orbital histiocytosis can cause limited eye movement, proptosis, decreased visual acuity, and epiphora. In this study, we review the novel findings regarding the pathophysiology, diagnosis, and treatment of different types of histiocytosis, focusing on their orbital manifestations., Method: This review was performed based on a search of the PubMed, Scopus, and Embase databases or relevant published papers regarding orbital histiocytosis on October 9th, 2023. No time restriction was proposed, and articles were excluded if they were not referenced in English., Results: 391 articles were screened, most of them being case reports. The pathophysiology of histiocytosis is still unclear. However, different mutations are found to be prevalent in most of the patients. The diagnostic path can be different based on various factors such as age, lesion site, type of histiocytosis, and the stage of the disease. Some modalities, such as corticosteroids and surgery, are used widely for treatment. On the other hand, based on some specific etiological factors for each type, alternative treatments have been proposed., Conclusion: Significant progress has been made in the detection of somatic molecular changes. Many case studies describe various disease patterns influencing the biological perspectives on different types of histiocytosis. It is necessary to continue investigating and clustering data from a broad range of patients with histiocytosis in children and adults to define the best ways to diagnose and treat these patients., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: 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., Purpose: This text provides an overview of histiocytoses as described in the WHO Classification 2022.

Crystal-storing histiocytosis (CSH) is a rare disorder that shows infiltration of histiocytes with an aberrant cytoplasmic accumulation of crystalline structures and is often accompanied by lymphoproliferative-plasma cell disorders (LP-PCD) as background diseases. The diagnosis of CSH requires identification of crystalline structures that accumulate in the infiltrating histiocytes, which may be challenging by optical microscopy alone. In this case report, we describe an atypical course of systemic CSH with multifocal fibrosclerosis of an unknown background disease that was diagnosed by ultrastructural observation, including transmission electron microscopy (TEM) and scanning electron microscopy (SEM), in pathological autopsy. In addition, crystalline structures were successfully identified by scanning electron microscopic observations using formalin-fixed and paraffin-embedded (FFPE) tissue from biopsy specimens taken before death. Since CSH was identified by SEM in a tiny biopsy specimen, observation of histiocytic infiltrative lesions by SEM using FFPE tissue may lead to early detection of and initiation of treatment for CSH., (© 2023. The Author(s) under exclusive licence to The Japanese Society for Clinical Molecular Morphology.)

Background: Crystal-storing histiocytosis (CSH), light chain proximal tubulopathy (LCPT), and light chain crystalline podocytopathy (LCCP) are rare complications of multiple myeloma (MM) or monoclonal gammopathy of renal significance, and their diagnoses are challenging., Case Presentation: In this case, a 69-year-old Chinese woman presented with suspicious Fanconi syndrome with renal insufficiency. Immunofixation electrophoresis of both serum and urine revealed elevated immunoglobulin G kappa (IgGkappa) and kappa light chain. Bone marrow aspirate revealed 15% plasma cells with considerable cytoplasmic granular inclusions and needle-shaped crystals. Renal biopsy confirmed the final pathologic diagnosis of kappa-restricted CSH, combined LCPT and LCCP by immunoelectron microscopy. A number of special casts were present which could easily be misdiagnosed as light chain cast nephropathy. Immunofluorescence on frozen tissue presented false negative for kappa light chain, as ultimately proven by paraffin-embedded tissue after pronase digestion. MM and CSH were diagnosed, and two cycles of chemotherapy were given. The patient subsequently refused further chemotherapy, and her renal function remained relatively stable during a 2.5-year follow-up period., Conclusions: In conclusion, we report a rare case of generalized kappa-restricted CSH involving bone marrow and kidney, combined with LCPT and LCCP, provide a comprehensive summary of renal CSH, and propose a new nomenclature of monoclonal immunoglobulin-induced crystalline nephrology. The presentation of monoclonal immunoglobulin and Fanconi syndrome should suggest the presence of monoclonal immunoglobulin-induced crystalline nephrology. Use of paraffin-embedded tissue after pronase digestion and immunoelectron microscopy is beneficial to improve the sensitivity of diagnosis.

Rationale: Diagnosing intralymphatic histiocytosis can be challenging due to its rarity. We present a case of intralymphatic histiocytosis in the upper eyelid of a Korean patient. We treated the condition by surgical debulking and intralesional triamcinolone injection., Patient Concerns: A 59-year-old man was referred to our clinic with a 7-year history of unilateral swelling in the right upper eyelid. He had previously been treated with long-term oral steroids and immunosuppressants, but his eyelid swelling persisted. Unilaterally non-pitting erythematous edema was localized on the right upper eyelid without any itching or pain. His best corrected visual acuity at presentation was 20/20 for both eyes. Enhanced orbital computerized tomography revealed edematous soft tissue thickening in the right upper eyelid. In the laboratory testing, the erythrocyte sedimentation rate showed an increase of 19, and the antinuclear antibody titer was positive with a homogeneous pattern., Diagnoses: We diagnosed the patient with intralymphatic histiocytosis based on the histopathological findings., Intervention: We attempted surgical debulking and biopsy on the right upper eyelid due to the persistent symptoms and the absence of a definitive diagnosis., Outcomes: The patient has demonstrated significant improvement after receiving an intralesional triamcinolone injection in the right upper eyelid following the surgery and is currently under follow-up with no signs of recurrence., Lesson: Ophthalmologists should consider intralymphatic histiocytosis in cases of persistent eyelid swelling that do not respond to treatment, even in Asian patients. Surgical debulking and intralesional triamcinolone injections may be beneficial for improvement., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Mutations in the SLC29A3 gene cause histiocytosis-lymphadenopathy plus (H) syndrome, a rare autosomal recessive genetic condition that affects numerous systems. We present a 7-year-old Syrian patient with pericardial effusion whose acute phase reactants did not decrease despite treatment. In order to emphasize the variety and raise awareness of H syndrome in the hopes of achieving an early diagnosis and appropriate treatment, molecular investigation of SLC29A3-related disorders is crucial. H syndrome is an uncommon genetic condition with a broad spectrum of phenotypes. Therefore, early genetic testing is essential for the accurate diagnosis of patients. Doctors should be aware of this condition and its symptoms and consider autoimmune diseases as a possible alternative diagnosis in patients with suspected immunodeficiency.

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., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

A 45-year-old female patient was found to have a nodule in the right lower lobe on physical examination. Chest CT showed the nodule was lobulated measuring 24 mm×23 mm, with obvious enhancement and adjacent pleural traction. As the PET-CT showed increased 18 F-FDG uptake suggesting malignancy, the wedge resection of the right lower lobe was performed. Grossly, the mass was adjacent to the pleural area with indistinct boundary. On cut sections, the lesion was solid and tough, with a greyish-pink colour. Microscopically, the lesion had an ill-defined margin, and was composed of spindle and polygonoid histiocytes with rich eosinophilic cytoplasm similar to rhabdoid muscle cells. The cytoplasm of histiocytes was filled with diamond-shaped or club-shaped crystals. Immunohistochemistry (IHC) showed the histiocytes were positive for CD68, κ, λ, IgG, IgM and IgA. The patient had been followed up for 41 months and had shown neither recurrences nor new diseases. CSH is a rare non-neoplastic histiocytic proliferative disease. Pulmonary CSH should be differentiated from multiple diseases. Accurate pathological diagnosis depends on its morphology and immunophenotype. This disease is often related to potential lymphoproliferative or plasma cell disorder. After diagnosis, a systemic examination is required and long-term follow-up is recommended.

Abstract: We report a noteworthy case of a 10-year-old girl who presented with papular and nodular lesions on the skin that were clinically and histologically mistaken for progressive nodular histiocytosis. During the clinical management of the patient, the high lipid levels raised the suspicion of lipid metabolism disease and helped us to make the correct diagnosis of sitosterolemia. In sitosterolemia, proper management such as restriction of plant sterol intake and administration of cholesterol absorption inhibitor can improve prognosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Abstract: Indeterminant cell histiocytosis (ICH) is a rare lymphoproliferative disorder that demonstrates features of Langerhans and non-Langerhans cell histiocytoses and diagnosis can be challenging. We present a case of a 62 year old woman with a generalized eruption of erythematous papules on the face, trunk and extremities. Skin biopsies demonstrated a dermal mononuclear cell infiltrate with monocytic (CD4, CD33), histiocytic (CD68, CD163), and dendritic cell (CD1a) immunophenotype but negative for Langerhans' cell marker (CD207). The differential diagnosis included leukemia cutis and ICH, and further workup revealed a normal bone marrow biopsy. To confirm the diagnosis of ICH, next generation sequencing with ETV3-NCOA2 gene fusion was performed and was positive. The patient's condition improved with methotrexate and narrow band UVB phototherapy. Our case adds to the existing literature supporting the use of next-generation sequencing to test for ETV3-NCOA2 gene fusion in suspected cases of ICH., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Among the histiocytic disorders, anaplastic lymphoma kinase (ALK)-positive histiocytosis emerged in 2008. As more and more cases of the novel entity are reported, our understanding of it is deepened. However, only a few cases with central nervous system (CNS) involvement have been reported. Furthermore, the lesion in the suprasellar region has not been documented.  CASE PRESENTATION: We presented a case of ALK-positive histiocytosis involving the suprasellar region of a one-year-and-four-month-old boy. Through clinical, neuropathological, and genomic analyses, the patient was diagnosed with ALK-positive histiocytosis. After lesions were resected he started treatment with a combination of the three compounds vincristine, prednisolone, and crizotinib, but they did not work. Cytarabine was then added as an additional chemotherapy drug for him, and the lesions in the brain and lungs were shrunk by combining treatment of crizotinib, dexamethasone, vincristine, and cytarabine according to the RECIST (esponse Evaluation Criteria In Solid Tumours)., Conclusions: Additional adjuvant chemotherapy drugs are needed when ALK-inhibitor treatment is ineffective., (© 2022. The Author(s).)

Histiocytic proliferations are heterogeneous lesions with distinct pathogenic and clinical-pathological features. While many of these conditions are nonspecific immune responses to variable causes, a minority of them is associated with specific etiological factors and unique clinical-pathological pictures. By presenting a rare case of Whipple adenopathy, we address the peculiar histological features of this condition and the differential diagnosis of nodal histiocytosis in general.

Introduction: Histiocytic disorders pose significant diagnostic and management challenges for the clinicians due to diverse clinical manifestations and often non-specific histopathologic findings. Herein, we report the tumor board experience from the first-of-its-kind Histiocytosis Working Group (HWG)., Materials and Methods: The HWG was established in June 2017 and consists of experts from 10 subspecialties that discuss cases in a multidisciplinary format. We present the outcome of tumor board case discussions during the first 2 years since its inception (June 2017-June 2019)., Results: Forty cases with a suspected histiocytic disorder were reviewed at HWG during this time period. Average number of subspecialties involved in HWG case discussion was 5 (range, 2-9). Histiocytosis Working Group tumor board recommendations led to significant changes in the care of 24 (60%) patients. These included change in diagnosis (n = 11, 27%) and change in treatment (n = 13, 33%)., Conclusion: Our report highlights the feasibility of a multidisciplinary tumor board and its impact on outcomes of patients with histiocytic disorders., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Intravascular histiocytosis is an underrecognized reactive skin condition characterized by the clinical finding of poorly demarcated erythematous to violaceous patches and plaques. The diagnosis is confirmed by the histologic findings of intraluminal histiocytes on skin biopsy and exclusion of an alternative diagnosis., Methods: A review of patients with a histologic diagnosis of intravascular or intralymphatic histiocytosis and seen at Mayo Clinic, Rochester, Minnesota, from January 1, 2010, to October 10, 2020, was performed. Histologic and clinical information was collected from the medical records., Results: Nine patients were identified. Clinical impressions prior to biopsy varied widely, and no clinician included intravascular histiocytosis in the initial clinical differential diagnosis. Eight patients had preceding trauma to the affected area., Conclusion: Intravascular histiocytosis remains a rare skin condition. Clinical identification remains low. Our cases add support to the hypothesis that intravascular histiocytosis is a reactive condition often preceded by trauma and/or surgery., (© 2021 the International Society of Dermatology.)

Purpose: To report a rare case of crystal-storing histiocytosis associated with solitary extramedullary plasmacytoma of the lacrimal sac and to review literature on the 2 entities to summarize important diagnostic, management, and prognostic considerations., Methods: A case report of the ophthalmologic presentation, pathology workup, and oncologic management is presented. Literature search with focus on lesions occurring in ophthalmic sites and management guidelines from expert panels and working groups., Results: Crystal-storing histiocytosis associated with solitary extramedullary plasmacytoma arose within the lacrimal sac of a previously healthy middle-aged woman and presented as a painless nodule with epiphora. The biopsy tissue showed sheets of crystal-filled histiocytes, interspersed with monoclonal plasma cells and rarely demonstrated plasma cell phagocytosis. Imaging and laboratory studies confirmed the localized nature., Conclusions: Crystal-storing histiocytosis is an uncommon entity in which crystals, most commonly arising from altered immunoglobulins, aggregate within histiocytes and form symptomatic mass lesions. It has been reported in ophthalmic regions in patients with a concurrent lymphoproliferative or plasma cell disorder and can rarely predate a malignancy. The current case is notable because crystal-storing histiocytosis occurs with a localized process, solitary extramedullary plasmacytoma, and presents in an unusual site, the lacrimal sac. Tissue biopsy with multimodal pathological evaluation is necessary to make the diagnosis. Ophthalmologists should recognize that crystal-storing histiocytosis is commonly associated with a hematologic malignancy and, when appropriate, refer the patient for oncologic management. Surveillance may be indicated in cases with no established etiology. Solitary extramedullary plasmacytoma should also be monitored, as a proportion of cases progress to multiple myeloma., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2021 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Anaplastic lymphoma kinase (ALK)-positive histiocytosis is a rare emerging entity characterized by systemic or localized proliferation of histiocytes harboring ALK rearrangements. Breasts are reportedly affected by ALK-positive histiocytosis. Here, we evaluated 2 localized cases of breast ALK-positive histiocytosis through a comprehensive clinicopathologic, molecular, and genomic analysis to further delineate this entity and better understand its pathogenesis. The cases involved 2 undiagnosed ALK-positive spindle-cell breast lesions. Both cases were Asian women aged 30s to 40s who underwent excisions for asymptomatic breast masses. Macroscopically, both lesions were well-circumscribed, solid masses. Microscopically, both lesions were predominantly composed of fascicles with uniform, bland spindle cells, admixed with epithelioid histiocyte-like cells and lymphoid aggregates. Immunohistochemically, the spindle and epithelioid cells coexpressed ALK and histiocytic markers (eg, CD68, CD163). Genetically, both lesions harbored KIF5B-ALK, confirmed by fluorescence in situ hybridization and polymerase chain reaction-direct sequencing analyses. Combining these results, both cases were successfully diagnosed as ALK-positive histiocytosis. Furthermore, no common or previously annotated somatic alterations were identified by whole-exome sequencing. One case harbored clonal immunoglobulin gene rearrangements according to the polymerase chain reaction-based BIOMED-2 protocol. Therefore, ALK-positive histiocytosis can be accurately diagnosed through a combination of morphologic, immunohistochemical, and molecular analyses. In this entity, breast cases may have distinct clinicopathologic features: Asian women aged 30s to 40s, asymptomatic masses, and predominant spindled morphology. For pathogenesis, ALK rearrangements could be the driver alteration, and a subset of ALK-positive histiocytosis may harbor a lymphoid lineage. These findings can be utilized to improve the diagnosis of ALK-positive histiocytosis and better understand its pathogenesis., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Aims: Histiocytoses are a heterogeneous group of localized or disseminated diseases. Clinical presentation and patients' outcome vary greatly, ranging from mild to life-threatening disorders. Rare cases of systemic or localized histiocytosis harboring ALK rearrangement have been reported., Methods: Two cases of CNS histiocytosis were thoroughly investigated by implementing multiple molecular tests, i.e. FISH, RT-qPCR, NGS analysis., Results: In a 10-month old girl (patient #1), MRI showed two left hemispheric lesions and a right fronto-mesial lesion histologically consisting of a moderately cellular infiltrative proliferation, composed by CD68(PGM1)+/CD163+ spindle cells. ALK 5'/3'-imbalance and a KIF5B(exon 24)-ALK(exon 20) fusion were documented by RT-qPCR and NGS analysis, respectively. A subsequent CT scan showed multiple hepatic and pulmonary lesions. The patient was started on chemotherapy (vinblastine) associated to an ALK-inhibitor (Alectinib) with remarkable response. In a 11-year-old girl (patient #2), MRI showed a right frontal 1.5 cm lesion. Neuropathological examination revealed a histiocytic proliferation composed by medium sized CD68(PGM1)+/HLA-DR+ cells, showing moderate ALK1 positivity. ALK rearrangement and a KIF5B(exon 24)-ALK(exon 20) fusion were demonstrated also in this case. Subsequent CT, 18F-FDG-PET and MRI scans showed the presence of a single right femoral lesion, proved to be a fibrous cortical defect., Conclusions: In ALK-histiocytoses, CNS involvement may occur as part of a systemic disease or, rarely, as its only primary disease localization, which could remain otherwise asymptomatic. The diagnosis often relies on neuropathological examination of brain biopsy, which may pose a diagnostic challenge due to the variable histopathological features. An integrated histological and molecular approach in such cases is recommended., (© 2021 British Neuropathological Society.)

ALK-positive histiocytosis was first described in 2008 as a systemic histiocytic disorder involving young infants and neonates. Subsequently, cases of local ALK-positive histiocytosis as well as clinical presentation in adult patients have been increasingly reported in the literature. The current case documented the hitherto largest local ALK-positive histiocytosis lesion involving the mesentery of a 20-year-old female patient, a clinical presentation that has not been previously reported in the medical literature. Of note was the presence of numerous lymphocytes, plasma cells, and eosinophils as well as the formation of lymphoid follicles in the lesion, mimicking an inflammatory myofibroblastic tumor. Other unique histologic aspects of the current case included the nested arrangement of the histiocytes, intravascular extension of the histiocytic proliferation into a large vein, and tumor necrosis. Notably, molecular studies revealed a novel TRIM33 (exon 12) -ALK (exon 20) gene fusion. Therefore, ALK-positive histiocytosis with TRIM33-ALK gene fusion expands the clinical, histologic, and molecular spectrum of local ALK-positive histiocytosis. Since ALK-positive histiocytosis associated with a significant inflammatory component can pose considerable diagnostic challenges, increased awareness of this peculiar variant of ALK-positive histiocytosis is essential to minimize the risk of misdiagnosis.