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Histiocytoses are rare diseases characterised by infiltration of affected organs by myeloid cells with a monocyte or dendritic cell phenotype. Symptoms can range from self-resolving localised forms to multisystemic lesions requiring specific treatment. To demonstrate extremely rare cases of CD68-negative cardiac histiocytosis with expression of SARS-CoV-2 antigen in infiltrate cells. We demonstrated a case of Erdheim-Chester disease in a 67-year-old man with pericardial involvement and positive dynamics with vemurafenib treatment, an autopsy case of xanthogranulomatous myopericarditis in a 63-year-old man, surgical material of xanthogranulomatous constrictive pericarditis in a 57-year-old man, and an autopsy case of xanthogranulomatosis in a 1-month-old girl. In all cases, xanthogranuloma cells expressed CD163, many of them spike protein SARS-CoV-2, while CD68 expression was detected only in single cells. In this article, we demonstrated four cases of extremely rare CD68-negative cardiac xanthogranulomatosis in three adults and one child with expression of the spike protein SARS-CoV-2 in M2 macrophages. This potential indirect association between COVID-19 and the development of histiocytosis in these patients warrants further investigation. To substantiate this hypothesis, more extensive research is needed.

Crystal-storing histiocytosis (CSH) is a rare condition in which crystals accumulate in the cytoplasm of histiocytes and is usually associated with a lymphoplasmacytic neoplasm. Cutaneous CSH is extraordinarily rare and limited to case reports in the literature. We report two cases of this disease with cutaneous involvement. Case 1 was a 65-year-old male with a 4-month history of a pruritic eruption that started as a solitary pink to skin-colored indurated plaque on the anterior neck before progressing to involve the whole neck, chest wall, and face. Case 2 was a 54-year-old woman with a history of unspecified "lymphoma" who presented with a soft nodule on the forearm. Biopsies from both cases had similar findings and showed a proliferation of epithelioid cells with pink cytoplasm and intracellular crystalline structures infiltrating the dermis and subcutaneous fat. In the first case, the cells were positive for CD43, CD45, CD68, and IgG kappa, and in the second case, the crystals were positive for IgG lambda. Based on these findings, the patients were diagnosed with cutaneous CSH. We highlight this rare diagnosis and the importance of investigating an underlying lymphoplasmacytic neoplasm., (© 2024 The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

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.)

Histiocytoses encompass a wide spectrum of diseases, all characterized by tissue infiltration by CD68+ histiocytes. Most adult histiocytoses are considered clonal diseases because they highlight recurrent somatic mutations in the MAP-kinase pathway gene, primarily BRAF . The presence of BRAF mutation is associated with widespread disease in children with Langerhans cell histiocytosis (LCH) or cardiovascular/neurological involvement in Erdheim-Chester disease (ECD). Nevertheless, few data are available on adult clonal histiocytosis. This is why we have conducted a retrospective study of all patients with clonal histiocytosis in our institution and present the data according to the presence of BRAF mutation. Among 27 adult patients (10 ECD, 10 LCH, 5 Rosai-Dorfman disease (RDD), and 3 mixed ECD/LCH), 11 (39%) have BRAF mutation with gain of function (n = 9) and deletion (n = 2). Those patients had frequent multicentric disease with risk organ involvement, especially the brain and cardiovascular system. They had frequent associated myeloid neoplasms (mostly chronic myelomonocytic leukemia) and received more frequently targeted therapy as the front-line therapy. Nevertheless, its presence did not affect the overall survival or relapse-free survival probably due to the emergence of efficient therapies. To conclude, rapid and accurate molecular establishment in adult clonal histiocytoses is crucial because BRAF V600E mutation correlates with multicentric disease with organ involvement and incomplete metabolic response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Razanamahery, Godot, Leguy-Seguin, Samson, Audia and Bonnotte.)

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.)

Abstract: S100-negative CD1a-positive cutaneous histiocytosis is an exceedingly rare histiocytosis that is defined histopathologically by a dense dermal infiltrate of ovoid mononuclear cells with grooved nuclei and ample cytoplasm with variable nuclear atypia and mitoses that are immunohistochemically positive for CD1a and negative for S100 and CD207 (langerin). The histogenesis of S100-negative CD1a-positive histiocytosis is unclear, and its precursor cell has yet to be characterized. Although all cases thus far have been described as benign and occasionally self-resolving, the clinical course and outcome of this disease are not fully understood. This case expands the spectrum of disease associated with S100-negative CD1a-positive histiocytosis given its malignant course., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

ALK-positive histiocytosis is a recently described entity with few reported cases in literature. Herein, we report an unusual case of ALK-positive histiocytosis showing an Erdheim-Chester disease (ECD)-like presentation, occurring in a 37-year-old woman with a 2-year history of chronic lymphocytic leukaemia (CLL). Our CLL patient relapsed 6 months after the end of fludarabine, cyclophosphamide and rituximab frontline therapy and complained of lower limb pains. A bone marrow biopsy was performed and showed concomitant CLL/small lymphocytic lymphoma and ALK-positive histiocytosis with an identical immunoglobulin heavy-chain gene rearrangement in both neoplasms, suggesting clonal relationship. After 4 years under ibrutinib therapy, our patient remains free of both diseases. This report extends the spectrum of composite hematolymphoid neoplasms and shows that ALK rearrangement should be considered in all histiocytosis subtypes. Moreover, both tumours eradication under ibrutinib suggests that BTK inhibitors may also be effective in histiocytic neoplasms.

ALK positive histiocytosis is a relatively new histiocytic proliferation disease with a characteristic gene translocation involving fusion of the ALK gene with different partners, mostly KIF5B. We report a case of ALK-positive histiocytosis with literature review. A 27-year-old male patient presented mainly with progressive lower limb weakness. Imaging studies showed an intradural extramedullary enhancing lesion at the L3 level. A 1.5 cm mass was excised from the sensory nerve root in the filum terminale at the level of L3. Histologic examination showed infiltration of the nerve by numerous histiocytes with moderate to abundant eosinophilic to clear-foamy and variably-vacuolated cytoplasm with irregular-to-smooth contoured nuclei. The histiocytes were positive for CD68 and ALK1 and negative for S100 and CD1a. KIF5B-ALK fusion was detected by real time-polymerase chain reaction. The patient is asymptomatic nine months after surgical excision. This is the first reported localized case occurring in the nerve root of an adult patient, thus expanding the clinical manifestations of this disease. An integrated histological, immunohistochemical and molecular approach is recommended for diagnosis. We recommend performing ALK1 immunohistochemical stain on all histiocytosis cases to increase awareness and detection of this newly described entity.

Crystal-storing histiocytosis (CSH) is a non-neoplastic histiocytic proliferation containing crystalline material, usually associated with an underlying lymphoproliferative or plasmacytic disorder. The crystalline structures are typically derived from kappa light chain immunoglobulins. The lesions of CSH are comprised of sheets of histiocytes with abundant eosinophilic cytoplasm containing variably prominent, elongated crystals. This rare phenomenon is important to recognize, as it is known to morphologically obscure an underlying neoplasm. Histologically, the cells of CSH may closely mimic Gaucher cells, as well as the "pseudo-Gaucher" cells sometimes encountered in chronic myeloid leukemia. The distinction between the cells of CSH and that of histologic mimics may be made more definitively through the use of electron microscopy, as the crystalline inclusions seen in CSH display characteristic size, shape, and localization within the cells. Here, we report 2 rare cases of CSH diagnosed by morphology, immunohistochemistry, and ultrastructural examination. The first case presented was diagnosed concurrently with plasma cell myeloma, and the second case discussed was diagnosed in association with marginal zone lymphoma.

Introduction: Chronic histiocytic intervillositis of unknown etiology (CIUE) is a non-infectious, most probably immunologic placenta lesion. CIUE is associated with recurrent miscarriage, intrauterine growth restriction and stillbirth. Among the pathologic-anatomic defined placental lesions this entity displays the highest risk of recurrence in following pregnancies (about 67-100%). The histiocytic cells accumulate in the placental blood space but do not infiltrate into the villi or decidua. Sparsely known is the expression profile of these intervillous cells regarding histiocytic markers., Methods: We analysed 5-22 markers by immunohistochemistry in a total of 41 placenta samples and evaluated decidual, villous and intervillous histiocytic cells., Results: In CIUE, intervillous CD163 +  histiocytes over-express CD11c/CD18 and down-regulate CD206/CD209, while CD163 +  decidual and Hofbauer cells show low CD11c/CD18 and higher CD206/CD209 protein expressions., Discussion: CD163 expression indicates a M2-like polarisation. CD11c and CD18 form the complement receptor 4 which could be related to a complement mediated trigger for aberrant cell accumulation in CIUE., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The term "H syndrome" was coined to denote the major clinical findings, which include hyperpigmentation, hypertrichosis, hearing loss, hepatosplenomegaly, hyperglycaemia, hypogonadism, hallux flexion contractures, and short height., Objective: To report the clinical, endocrinological, histochemical, and genetic findings of three siblings., Methods: Skin and liver biopsies were taken to investigate the histochemical characteristics of hyperpigmented hypertrichotic skin lesions and massive hepatomegaly. The levels of basal serum thyroid hormones, oestradiol, total testosterone, follicle-stimulating hormone, luteinising hormone, and stimulated growth hormone (GH) were measured to investigate the endocrine aspects of the syndrome. Mutation analysis was carried out in all six exons and exon-intron boundaries of SLC29A3 by direct sequencing., Results: Physical examination of the patients revealed common charac-teristic findings of H syndrome. Additional clinical findings were sectorial iris atrophy in the younger sister. Laboratory evaluation revealed microcytic anaemia, markedly increased erythrocyte sedimentation rate and C-reactive protein levels, and humoral immune deficiency in the younger siblings, who presented with recurrent fever and sinopulmonary infection. Two different GH stimulation tests revealed GH deficiency in the younger sister with short stature. Liver and skin biopsies revealed polyclonal lymphohistiocytic and plasma cell infiltration. Sequencing of SLC29A3 in the three siblings revealed a novel homozygous mutation in exon 6, which caused the transition of arginine to tryptophan., Conclusion: This study not only extended the clinical and mutation spectrum of SLC29A3 in H syndrome, but also showed that short children should be assessed according to the guidelines for short stature in children., (© 2019 S. Karger AG, Basel.)

The bone marrow is a preferential site for both reactive and neoplastic histiocytic proliferations. The differential diagnosis ranges from reactive histiocyte hyperplasia in systemic infections, vaccinations, storage diseases, post myeloablative therapy, due to increased cell turnover, and in hemophagocytic lymphohistiocytosis, through extranodal Rosai-Dorfman disease to neoplasms derived from histiocytes, including histiocytic sarcomas (HS), Langerhans cell histiocytoses (LCH), Erdheim-Chester disease (ECD), and disseminated juvenile xanthogranuloma (JXG). One of the most important recent developments in understanding the biology of histiocytic neoplasms and in contributing to diagnosis was the detection of recurrent mutations of genes of the Ras/Raf/MEK/ERK signaling pathway, in particular the BRAF V600E mutation, in LCH and ECD. Here, we summarize clinical and pathological findings of 17 histiocytic neoplasms that were presented during the bone marrow symposium and workshop of the 18th European Association for Haematopathology (EAHP) meeting held in Basel, Switzerland, in 2016. A substantial proportion of these histiocytic neoplasms was combined with clonally related lymphoid (n = 2) or myeloid diseases (n = 5, all ECD). Based on the latter observation, we suggest excluding co-existent myeloid neoplasms at initial staging of elderly ECD patients. The recurrent nature of Ras/Raf/MEK/ERK signaling pathway mutations in histiocytic neoplasms was confirmed in 6 of the 17 workshop cases, illustrating their diagnostic significance and suggesting apotential target for tailored treatments.

ALK-positive histiocytosis is a recently described rare histiocytic proliferative disorder of early infancy. When infants present with anemia, thrombocytopenia, and hepatosplenomegaly, this entity should be included in the differential diagnosis along with hemophagocytic lymphohistiocytosis, metabolic/storage diseases, hematopoietic malignancies, and autoimmune thrombocytopenia. We report 2 new cases of ALK-positive histiocytosis, one with kidney involvement and the other with extensive bone marrow involvement in addition to an overt liver disease. Renal involvement by ALK-positive histiocytosis has not been reported. The infiltrating histiocytes in this case showed Rosai-Dorfman disease-like morphology including emperipolesis. The histiocytes in the second case with extensive bone marrow involvement had foamy cytoplasm initially suggesting storage disease. Our 2 cases highlight previously unrecognized diversity of ALK-positive histiocytosis in clinical manifestation, organ involvement, and cytomorphologic features and further elucidate the diagnostic challenges of this rare entity.

Distinguishing classical dendritic cells from other myeloid cell types is complicated by the shared expression of cell surface markers. ZBTB46 is a zinc finger and BTB domain-containing transcription factor, which is expressed by dendritic cells and committed dendritic cell precursors, but not by plasmacytoid dendritic cells, monocytes, macrophages, or other immune cell populations. In this study, we demonstrate that expression of ZBTB46 identifies human dendritic cell neoplasms. We examined ZBTB46 expression in a range of benign and malignant histiocytic disorders and found that ZBTB46 is able to clearly define the dendritic cell identity of many previously unclassified histiocytic disease subtypes. In particular, all examined cases of Langerhans cell histiocytosis and histiocytic sarcoma expressed ZBTB46, while all cases of blastic plasmacytoid dendritic cell neoplasm, chronic myelomonocytic leukemia, juvenile xanthogranuloma, Rosai-Dorfman disease, and Erdheim-Chester disease failed to demonstrate expression of ZBTB46. Moreover, ZBTB46 expression clarified the identity of diagnostically challenging neoplasms, such as cases of indeterminate cell histiocytosis, classifying a fraction of these entities as dendritic cell malignancies. These findings clarify the lineage origins of human histiocytic disorders and distinguish dendritic cell disorders from all other myeloid neoplasms.

The pathophysiology of neurodegenerative diseases is poorly understood and there are few therapeutic options. Neurodegenerative diseases are characterized by progressive neuronal dysfunction and loss, and chronic glial activation. Whether microglial activation, which is generally viewed as a secondary process, is harmful or protective in neurodegeneration remains unclear. Late-onset neurodegenerative disease observed in patients with histiocytoses, which are clonal myeloid diseases associated with somatic mutations in the RAS-MEK-ERK pathway such as BRAF(V600E), suggests a possible role of somatic mutations in myeloid cells in neurodegeneration. Yet the expression of BRAF(V600E) in the haematopoietic stem cell lineage causes leukaemic and tumoural diseases but not neurodegenerative disease. Microglia belong to a lineage of adult tissue-resident myeloid cells that develop during organogenesis from yolk-sac erythro-myeloid progenitors (EMPs) distinct from haematopoietic stem cells. We therefore hypothesized that a somatic BRAF(V600E) mutation in the EMP lineage may cause neurodegeneration. Here we show that mosaic expression of BRAF(V600E) in mouse EMPs results in clonal expansion of tissue-resident macrophages and a severe late-onset neurodegenerative disorder. This is associated with accumulation of ERK-activated amoeboid microglia in mice, and is also observed in human patients with histiocytoses. In the mouse model, neurobehavioural signs, astrogliosis, deposition of amyloid precursor protein, synaptic loss and neuronal death were driven by ERK-activated microglia and were preventable by BRAF inhibition. These results identify the fetal precursors of tissue-resident macrophages as a potential cell-of-origin for histiocytoses and demonstrate that a somatic mutation in the EMP lineage in mice can drive late-onset neurodegeneration. Moreover, these data identify activation of the MAP kinase pathway in microglia as a cause of neurodegeneration and this offers opportunities for therapeutic intervention aimed at the prevention of neuronal death in neurodegenerative diseases.

Reactive angioendotheliomatosis (REA) is a rare benign angioproliferative condition of the skin, which has been noted to occur in patients with a variety of underlying systemic diseases. Histopathologically, this condition is characterized by vascular proliferation, and endothelial cell hyperplasia within the lumina and around dermal vessels, without significant cellular atypia. Since the first case of RAE was reported in 1958, multiple histologic patterns of benign cutaneous vascular proliferations with similar clinical presentations to RAE have been described in the literature and have been proposed as subtypes of the originally described condition. Among these entities are diffuse dermal angiomatosis (DDA), acroangiodermatitis, glomeruloid angioendotheliomatosis, and angiomatosis associated with cryoproteins. It has also been proposed that another entity, characterized by the benign proliferation of histiocytes within the lumina of cutaneous vessels, is a subtype of RAE. Histiocytosis within dermal vessels, in conjunction with skin pathology, was first reported in 1994. Based on the appearance of involved vessels, it was initially believed that the histiocytic proliferations were within the lumina of capillaries. Hence, the term intravascular histiocytosis was introduced to describe this histologic finding. However, subsequent introduction of an immunohistochemical (IHC) marker specific for lymphatic vessels demonstrated that most cases of cutaneous histiocyte proliferation are intralymphatic, rather than truly intravascular. However, there have also been reports of IHC-confirmed cases of true intravascular (intracapillary) histiocytosis. In this study, clinical and histologic data from all of the cases of RAE and IHC-confirmed cases of intravascular histiocytosis and intralymphatic histiocytosis reported in the literature to date are examined. Through comparison of the frequency with which key clinical and histologic features present in cases of each group, the authors provide improved clarity of the similarities and differences between these 3 entities.

Multicentric reticulohistiocytosis (MRH) is a rare and debilitating systemic disorder characterized by cutaneous nodules and destructive polyarthritis. Due to its unknown etiology, the treatment of MRH varies with different rates of success, which causes treatment options to be rather independent and empirical. In the present study, a case of a 48‑year‑old woman with a 12‑month history of polyarthralgia and skin nodules was reported. Biopsy samples, which were obtained from her skin eruption exhibited dermal infiltration with histiocytes and multinucleated giant cells. Immunohistochemical staining indicated positivity for CD68. The patient was diagnosed with MRH and treated with a combination therapy of infliximab, prednisolone and methotrexate. Her symptoms improved markedly within 2 weeks. Following the results of this case study, a systematic review of 17 cases of MRH treated with tumor necrosis factor (TNF) antagonists was performed, and the efficacy of anti‑TNF treatment in MRH was analyzed.

Background: Crystal storing histiocytosis (CSH) is a rare disorder characterized by accumulation of histiocytes containing crystalline material inclusions. This entity can be misdiagnosed as infection or tumor. We present a case of idiopathic CSH mimicking metastatic squamous cell carcinoma in a cervical lymph node and review of literature regarding this rare entity., Methods and Results: The patient was a 70-year-old man with a medical history of squamous cell carcinoma of the right base of the tongue. The patient presented with an enlarged cervical lymph node, which was clinically diagnosed as metastatic carcinoma. At intraoperative consultation, it was unexpectedly discovered that the lymph node exhibited extensive histiocytosis containing crystal materials. Final pathology identified "crystal storing histiocytosis" because of amyloidal depositions. No metastatic carcinoma was seen., Conclusion: After 10 months of follow-up, the patient is disease free. To the best of our knowledge, this unusual clinical presentation is the first to describe CSH mimicking a metastatic carcinoma., (© 2015 Wiley Periodicals, Inc.)

Crystal storing histiocytosis (CSH) is a rare condition where crystals accumulate in the cytoplasm of macrophages and is usually associated with a lymphoplasmacytic neoplasm producing a monoclonal immunoglobulin with kappa light chain. CSH with primary manifestation in the skin is extraordinarily rare and limited to four case reports in the literature. Here we present two cases of cutaneous CSH. One case is that of an 80 year old woman who presented with bilateral periorbital oedema with yellow discolouration. Skin biopsy showed dermal CSH in association with a neoplastic lymphoplasmacytoid infiltrate showing IgM kappa light chain restriction. Subsequent work up led to the discovery of Waldenstrom's macroglobulinemia. She had an indolent clinical course but died 6 years later from transformation into a diffuse large B cell lymphoma in the bone marrow. The other case is that of a 52 year old man who was recently diagnosed with multiple myeloma and developed a pruritic rash on his back during chemotherapy. Skin biopsy showed Grover disease (transient acantholytic dermatosis) and crystal storing macrophages in the superficial dermis. He died 4 years later after a protracted clinical course involving multiple cycles of chemotherapy and numerous complications. In both patients cutaneous CSH occurred early in the course of their lymphoplasmacytic malignancy and its development did not herald rapid clinical decline., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

A humanized TLR7/TLR8 transgenic mouse line was engineered for studies using TLR7/8 ligands as vaccine adjuvants. The mice developed a spontaneous immune-mediated phenotype prior to six months of age characterized by runting, lethargy, blepharitis, and corneal ulceration. Histological examination revealed a marked, multisystemic histiocytic infiltrate that effaced normal architecture. The histological changes were distinct from those previously reported in mouse models of systemic lupus erythematosus. When the mice were crossed with MyD88-/- mice, which prevented toll-like receptor signaling, the inflammatory phenotype resolved. Illness may be caused by constitutive activation of human TLR7 or TLR8 in the bacterial artificial chromosome positive mice as increased TLR7 and TLR8 expression or activation has previously been implicated in autoimmune disease.

Granular cell astrocytoma (GCA) is an uncommon malignant glial tumour that is associated with a poor prognosis. GCA cells have some morphological and immunohistochemical similarities to macrophages. In this case, a small biopsy contained no typical astrocytoma and large rounded lesional cells were interpreted as negative for glial fibrillary acidic protein and S100 and positive for CD68, a commonly used marker for macrophages. A diagnosis of a histiocytosis was made. When the patient failed to respond to first and second line therapy, tumour resection was undertaken and the pathology then showed typical morphologic and immunohistochemical features of glioblastoma (astrocytoma World Health Organization grade IV)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

A case of crystal-storing histiocytosis (CSH) associated with mucosa-associated lymphoid tissue (MALT) lymphoma of orbit is reported. The patient was a 53-year-old man who presented with an 8-year history of a slowly enlarging tumor in his right orbit. Histopathologic examination revealed that the tumor was composed predominantly of sheets of spindle-shaped cells resembling striated muscle cells and scattered aggregates of atypical lymphoid cells, showing prominent plasmacytoid differentiation. Immunohistochemical analysis demonstrated that the spindle-shaped cells were CD68-positive histiocytes containing abundant crystals in their cytoplasm, consistent with the diagnosis of CSH. The aggregates of atypical lymphoid cells were diagnosed as MALT lymphoma based on their immunophenotype. Although CSH is a well-recognized manifestation in lymphoproliferative disorders, CSH complicated by MALT type of ocular adnexal lymphoma has rarely been reported. Given the rarity of this, every case presenting with such crystal-storing histiocytes warrants a thorough search for a hidden lymphoid dyscrasia.

Background: Intralymphatic histiocytosis (IH) is a rare condition often associated with systemic disease. A benign condition, clinical presentations can vary greatly and its cause is largely unknown. Histologically, there are macrophages within distended lymphatic vessels, although this can be an incidental finding or the primary abnormality., Objective: We present a series of 7 cases of IH with and without disease associations, and a review of the literature. We propose IH as either primary (without associated conditions) or secondary (associated with systemic disease)., Methods: This was a retrospective collection of patients whose skin biopsy specimens revealed intralymphatic collections of histiocytes. We reviewed their clinical presentation, disease associations, and staining of slides with CD68 in all cases, D2-40 in 5 cases, and HLA-DR in 4 cases., Results: Clinical features were highly variable, and not all cases were associated with systemic disease. One case had admixed reactive angioendotheliomatosis. All 4 cases stained for HLA-DR showed strong expression by the intralymphatic macrophages., Limitations: Retrospective analysis and limited numbers are limitations., Conclusion: IH is not always associated with systemic disease although macrophage activation nevertheless implies immune activation., (Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Crystal storing histiocytosis (CSH) is a rare disorder characterized by the accumulation of crystalline material in the cytoplasm of histiocytes. Involvement of the central nervous system (CNS) with CSH is extremely rare. Herein, we report a case of crystal storing histiocytosis involving the CNS. Using immunohistochemistry and mass spectrometry we demonstrate that the disease resulted from an IgA-κ restricted plasma cell dyscrasia. CNS-CSH represents a rare clinicopathologic entity with an indolent course, usually lacking systemic manifestations.

Histiocytic proliferative disorders are commonly observed in dogs and less often cats. Histiocytic disorders occur in most of the dendritic cell (DC) lineages. Canine cutaneous histiocytoma originates from Langerhans cells (LCs) indicated by expression of CD1a, CD11c/CD18, and E-cadherin. When histiocytomas occur as multiple lesions in skin with optional metastasis to lymph nodes and internal organs, the disease resembles cutaneous Langerhans cell histiocytosis of humans. Langerhans cell disorders do not occur in feline skin. Feline pulmonary LCH has been recognized as a cause of respiratory failure due to diffuse pulmonary infiltration by histiocytes, which express CD18 and E-cadherin and contain Birbeck's granules. In dogs and cats, histiocytic sarcomas (HS) arise from interstitial DCs that occur in most tissues of the body. Histiocytic sarcomas begin as localized lesions, which rapidly disseminate to many organs. Primary sites include spleen, lung, skin, brain (meninges), lymph node, bone marrow, and synovial tissues of limbs. An indolent form of localized HS, progressive histiocytosis, originates in the skin of cats. Hemophagocytic HS originates in splenic red pulp and bone marrow macrophages in dogs and cats. In dogs, histiocytes in hemophagocytic HS express CD11d/CD18, which is a leuko-integrin highly expressed by macrophages in splenic red pulp and bone marrow. Canine reactive histiocytic diseases, systemic histiocytosis (SH) and cutaneous histiocytosis, are complex inflammatory diseases with underlying immune dysregulation. The lesions are dominated by activated interstitial DCs and lymphocytes, which invade vessel walls and extend as vasocentric infiltrates in skin, lymph nodes, and internal organs (SH).

Recent studies highlight surprising roles for granulocyte-macrophage colony-stimulating factor (GM-CSF) production by T cells. T-cell-derived GM-CSF is required for the differentiation of monocyte-derived inflammatory dendritic cells during inflammation and for the pathogenicity of IL-17 producing T helper cells in autoimmunity. To gain further insight into these findings, we engineered in vivo overexpression of GM-CSF specifically in T cells, under the control of the Lck promoter. Lck-GM-CSF transgenic mice displayed a dramatic phenotype, characterized by splenomegaly, lymphadenopathy, thymic atrophy, and multiple abnormalities in blood cell populations. Thymocyte differentiation was severely affected, and there was a dramatic increase in regulatory T cells in the thymus and peripheral lymphoid organs. Lck-GM-CSF transgenic mice developed a disseminated histiocytosis and had increased circulating IL-17 producing T helper cells-related cytokines. The pathological characteristics in Lck-GM-CSF transgenic mice resemble those of histiocytic human diseases, such as Langerhans cell histiocytosis. The etiology of many histiocytic disorders is unknown, but our findings suggest that over-production of GM-CSF by T cells could be a pathogenic factor and raise the possibility that GM-CSF may represent a novel therapeutic target., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Crystal-storing histiocytosis is an uncommon form of nonneoplastic histiocytic proliferation that in most patients complicates an underlying lymphoproliferative or plasma cell disorder. Lung is a common site of involvement in patients with localized disease. We present an illustrative example from a 54-year-old woman with an asymptomatic solitary lung nodule. The tumor was characterized by sheets of histiocytes with abundant cytoplasm expanded by distinctive eosinophilic inclusions. Focal necrosis was present. Aggregates of monocytoid lymphocytes and clusters of peribronchiolar plasma cells were overshadowed by the histiocytic infiltrate. Immunohistochemical stains showed CD68 staining in nonneoplastic histiocytes and CD20 staining in monocytoid lymphocytes. In situ hybridization studies showed κ light-chain restriction in plasma cells. These results, combined with the histologic findings, supported the diagnosis of crystal-storing histiocytosis complicating marginal zone lymphoma of mucosa-associated lymphoid tissue. We review the literature pertaining to pulmonary crystal-storing histiocytosis, highlighting the differential diagnosis for this rare phenomenon.

Background: Sox10 is a transcription factor associated with neural crest development. Its expression has been reported in melanocytes and peripheral nerve sheath cells and their associated tumors., Objective: To assess Sox10 sensitivity in benign and malignant melanocytic neoplasms of various histologic subtypes and to discern the specificity of Sox10 in distinguishing between melanocytic neoplasms and fibrohistiocytic and histiocytic mimickers., Methods: Sox10 expression was examined by immunohistochemistry in 145 cases of formalin-fixed paraffin-embedded tissue, including benign and malignant melanocytic lesions of various histologies and stages (n = 83), fibrohistiocytic and histiocytic lesions (n = 33), and peripheral nerve sheath tumors (n = 19), among others (n = 10)., Results: Immunoreactivity with Sox10 was observed in 100% (83/83) of benign and malignant melanocytic lesions of various subtypes, as well as in 100% (19/19) of benign and malignant peripheral nerve sheath lesions. Among the fibrohistiocytic proliferations and histiocytoses examined, Sox10 was negative in all cases (0/33). Sox10 expression did not vary by histologic subtype in nevi or melanoma; however, both the percentage of tumor nuclei demonstrating Sox10 expression and the intensity of expression were inversely correlated with malignant potential (nevi, melanoma in situ, invasive and metastatic melanoma) (P < .001, P = .016, respectively). Malignant peripheral nerve sheath tumors also showed decreased mean Sox10 expression and decreased intensity of expression when compared with benign counterparts (P < .001, P = .021, respectively)., Limitations: This is a retrospective study with 145 cases included., Conclusions: Sox10 is a highly sensitive marker for melanocytic proliferations and may be useful diagnostically when the differential diagnosis includes fibrohistiocytic and histiocytic proliferations demonstrating S100 expression., (Copyright © 2012 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

CSH is a very uncommon lesion and is distinctly unusual in the brain. We report a case of CSH within the brain parenchyma in a 27-year-old woman with Crohn disease. Advanced radiologic imaging and anatomic pathology correlation allow this report to serve as a reference for future similar cases.

Cytophagic histiocytic panniculitis (CHP) is a rare disease mostly caused by viral infections and/or lymphoproliferative diseases. We describe a case of CHP associated with H1N1 vaccine during the winter 2009-2010 vaccination campaign and discuss the cutaneous side effects of influenza vaccines. A 6-year-old child presented with inflammatory subcutaneous nodules, which had appeared 1 month after the first injection of H1N1 vaccine and 1 week after the second injection. There was no history of recent infection. The skin lesions spontaneously disappeared without scarring. In CHP the abnormal cytokine secretion from neoplastic or reactive T cells promotes monocyte-macrophage activation and haemophagocytosis. Vaccination is not a common cause of CHP, but it seems possible that, as in infectious diseases, reactive T cells to the vaccine antigen could trigger CHP., (Copyright © 2011 S. Karger AG, Basel.)

Crystal-storing histiocytosis is a rare disorder that is typically associated with low-grade B-cell lymphomas and monoclonal gammopathy. We present a 64-year-old man with a prior history of weakness and weight loss and hematologic evaluation that had revealed immunoglobulin G kappa monoclonal light chains in the serum and negative bone marrow biopsy. He presented with supraventricular tachyarrhythmia and a right atrial mass seen on echocardiogram and excised surgically. Histologically, the tumor was composed of sheets of macrophages infiltrating the atrial myocardium. The histiocytes were filled with multiple needle-shaped, periodic acid-Schiff-negative crystals. These cells and associated plasma cells failed to show clonal light chain restriction by in situ hybridization or immunohistochemistry, and there was no area of lymphoma in the tumor. Ultrastructural examination showed numerous stick-like, trapezoidal, or polygonal dense crystals in the cytoplasm of histiocytes corroborating the diagnosis of crystal-storing histiocytosis. Although rare, crystal-storing histiocytosis should be included in the differential diagnosis of heart masses in patients with hematologic conditions associated with monoclonal gammopathy.

Intralymphatic histiocytosis is a rare condition characterized by the presence of dilated lymphatic vessels containing aggregates of mononuclear histiocytes (macrophages) within their lumina. The phenomenon seems to occur almost exclusively within the reticular dermis. Although its pathogenesis remains uncertain, there has been speculation about the possible relationship between intralymphatic histiocytosis and intravascular reactive angioendotheliomatosis. In addition, several examples historically have been associated with rheumatoid arthritis. We describe our experience with 16 cases of intralymphatic histiocytosis. Clinically, the lesions were located predominantly on the upper and lower limbs, and they consisted of asymptomatic and poorly demarcated erythematous plaques and livedo reticularis-like lesions. They were characterized histopathologically by dilated vascular structures involving the reticular dermis. Some of these dilated vessels had empty lumina, whereas others contained variable number of mononuclear histiocytes. An inflammatory response of variable intensity from case to case was also present in the adjacent dermis. The dilated vessels exhibited thin walls with irregular shapes, and a single discontinuous layer of flat endothelial cells lined their lumina. Immunohistochemically, the endothelial cells lining the dilated lumina expressed immunoreactivity for CD31, CD34, podoplanin, D2-40, Lyve-1, and Prox-1, which confirmed their nature as lymphatic endothelial cells. Intralymphatic mononuclear histiocytes expressed CD68 (PGM1), although some cases also had variable immunoexpression for myeloperoxidase, CD31, and podoplanin. In the 4 cases that employed double immunohistochemistry, with podoplanin + CD68 (PGM1) or with Lyve-1 + CD68 (PGM1), each marker highlighted their specific target cells unequivocally; the endothelial cells expressed podoplanin or Lyve-1 immunoreactivity, and intralymphatic histiocytes showed CD68 (PGM1) immunoexpression. Our findings expand on the previously described morphologic and immunohistochemical features of intravascular histiocytosis. We also discuss the possible relationship between intralymphatic histiocytosis and the so-called reactive intravascular angioendotheliomatosis.

A 52-year-old man, with a known case of multiple myeloma, developed chronic bilateral pulmonary infiltration. Open lung biopsy displayed desquamated interstitial pneumonia-like pattern characterized by diffused patchy intra-alveolar accumulation of unusual macrophages containing abundant round intracytoplasmic eosinophilic globular structures 1-7 microm in size. The globules were stained positively with restriction for kappa light chain by immunoperoxidase study. Electron microscopic examination revealed amorphous substances without a crystalline shape or fine ultrastructure of lattice or linear parallel configuration, indicating storage of noncrystallized immunoglobulin. The current report documented, for the first time, the noncrystallized form of immunoglobulin-storing histiocytosis, causing an unusual pulmonary pathology in a patient with multiple myeloma.