Cutaneous crystal storing histiocytosis: A case series with review of literature.

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.

CD68-Negative Histiocytoses with Cardiac Involvement, Associated with COVID-19.

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.

A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease.

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.

A novel approach to diagnosing crystal-storing histiocytosis: utility of scanning electron microscopy for formalin-fixed paraffin-embedded tissue specimens.

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.

ALK-Positive Histiocytosis with Peripheral Blood Histiocytes: A Case Report.

Histiocytoses are a diverse group of rare, clinically heterogeneous disorders characterised by tissue infiltration of histiocytes, which may result in organ dysfunction and failure. Over 100 different subtypes of histiocytoses have been recognised, including rare cases of ALK-positive histiocytosis. We report a case of histiocytosis in a neonate who presented with refractory thrombocytopenia, anaemia, and intermittent neutropenia. Histiocytes were present in both peripheral blood smears and bone marrow; ALK positivity was demonstrated by immunohistochemistry. Given the scarce reports of this condition, the variable organ involvement, and the different approaches to management in the cases described, we seek to expand the literature by providing a report of our patient whose condition improved without chemotherapy. The presence of histiocytes in peripheral blood smears of patients with this condition has not previously been reported, and it underscores the importance of routine careful evaluation of blood smears.

Leukemia Cutis With Histopathologic and Immunophenotypic Features Resembling S100-Negative CD1a-Positive Cutaneous Histiocytosis.

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.

A case of S-100-negative CD1a-positive indeterminate cell histiocytosis.

Histiocytoses are a group of rare disorders characterized by a proliferation of monocytes/macrophages and dendritic cells. We present a case of a 3-year-old girl with a diffuse papular eruption without systemic symptoms demonstrating a proliferation of strongly CD1a+ histiocytes, but negative for S-100 and langerin on histopathology. Systemic work-up including bone marrow biopsy was unremarkable, and the patient received a diagnosis of CD1a+ S- 100-indeterminate cell histiocytosis.

Expression of the transcription factor ZBTB46 distinguishes human histiocytic disorders of classical dendritic cell origin.

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.

Histiocytic cell neoplasms involving the bone marrow: summary of the workshop cases submitted to the 18th Meeting of the European Association for Haematopathology (EAHP) organized by the European Bone Marrow Working Group, Basel 2016.

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 BRAFV600E 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.

Differentiating Intralymphatic Histiocytosis, Intravascular Histiocytosis, and Subtypes of Reactive Angioendotheliomatosis: Review of Clinical and Histologic Features of All Cases Reported to Date.

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.

Intralymphatic histiocytosis comprises M2 macrophages in superficial dermal lymphatics with or without smooth muscles.

Intralymphatic histiocytosis represents a rare reactive disorder, which is characterized by the accumulation of macrophages within lymphatic vessels and observed predominantly in upper extremities. The infiltration and preferential M2 differentiation of macrophage are observed in chronic lymphedema, and lymphedema is considered a causative factor of intralymphatic histiocytosis. However, what causes accumulation of histiocytes in the lymphatic vessels remains unclear, and investigation regarding the characteristics of the macrophages has not been evaluated. We present a case of intralymphatic histiocytosis, in which immunohistochemical staining for both macrophages and lymphatic vessels was performed to evaluate the nature of macrophages within lymphatic vessels and to determine the causative factor. Aggregated macrophages were shown to be M2 macrophages positive for CD68, CD163 and CD206 but negative for inducible nitric oxide synthase. Thick lymphatic vessels positive for D2-40 and α-SMA in the superficial dermis were observed. We speculate that chronic lymphedema leads to hypertrophy of lymphatic vessels with smooth muscle in the superficial dermis, which may be a kind of malformation, and these lymphatic vessels produce some chemokines that induce intralymphatic aggregation of macrophages.

Transgenic expression of GM-CSF in T cells causes disseminated histiocytosis.

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.

Cutaneous crystal storing histiocytosis: a report of two cases.

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.

Primary and secondary intralymphatic histiocytosis.

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.

IgA/kappa-restricted crystal storing histiocytosis involving the central nervous system characterized by proteomic analysis.

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.

A review of histiocytic diseases of dogs and cats.

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).