[Erdheim-Chester disease initially discovered at extraskeletal locations: a clinicopathological analysis of four cases].

Objective: To investigate the clinicopathological features of Erdheim-Chester disease (ECD) initially diagnosed at extraskeletal locations. Methods: Clinical and pathological data of four cases of ECD diagnosed initially in extraskeletal locations were collected at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2013 to June 2023. BRAF V600E gene was detected by reverse transcription polymerase chain reaction (RT-PCR). Pertinent literatures were reviewed. Results: Four ECD patients included two males and two females ranging in ages from 2 years 11 months to 69 years. The lesions located in the lung (two cases), central nervous system (one case), and the testicle (one case) were collected in the study. One patient had occasional fever at night, one had nausea and vomiting, and two were asymptomatic. Radiologically, the two pulmonary ECD showed diffuse ground-glass nodules in both lungs, and the lesions in central nervous system and testicle both showed solid masses. Microscopically, there were infiltration of foamy histiocyte-like cells and multinucleated giant cells in a fibrotic background, accompanied by varying amounts of lymphocytes and plasma cells. The infiltration of tumor cells in pulmonary ECD was mainly seen in the subpleural area, interlobular septa, and perivascular and peribronchiolar areas. The fibrosis was more pronounced in the pleura and interlobular septa, and less pronounced in the alveolar septa. Immunohistochemical staining showed that all tumor cells expressed CD68, CD163 and Fô€ƒ¼a; one case showed S-100 expression; three cases were positive for BRAF V600E; all were negative for CD1α and Langerin. RT-PCR in all four cases showed BRAF V600E gene mutation. Conclusions: Extraskeletal ECD is often rare and occult, and could be easily misdiagnosed, requiring biopsy confirmation. The radiologic findings of pulmonary ECD is significantly different from other types of ECD, and the histopathological features of pronounced infiltration in the subpleura area, interlobular septa, perivascular and peribronchiolar areas can be helpful in the differential diagnosis from other pulmonary diseases. Detection of BRAF V600E gene mutation by RT-PCR and its expression by immunohistochemical staining are also helpful in the diagnosis.

Facial cutaneous Rosai-Dorfman disease: a case report.

BACKGROUND: Rosai-Dorfman disease (RDD) is a form of non-Langerhans cell histiocytosis in which the activated histiocytes of the lymph nodes and other organs begin to accumulate following excessive production. Bilateral, massive, and painless lymphadenopathy are classic presentations. Systemic RDD is already known to be a rare condition, but isolated cutaneous RDD is extremely rare. We presented a rare and unusual presentations of a disease. CASE PRESENTATION: A 35-year-old Thai female with a 6-month history of a small acne-like lesion that rapidly progressed to 5 cm tumor-like lesions on the face within 3 months. Tissue histology showed a dense dermal infiltration of histiocytes with emperipolesis phenomenon. Immunohistochemistry was positive for S100 protein and CD68 and negative for CD1a. Oral prednisolone (50 mg/day) was initiated with a favorable outcome at the one-month follow-up. However, prednisolone yielded a partial response at 2-month follow-up, leading to application of another modality. CONCLUSION: Although cutaneous Rosai-Dorfman disease is considered benign and well medical responded disease, patients with atypical presentation and rapid growing lesion may necessitate aggressive multimodal treatment.

Systemic xanthogranuloma involving bone marrow and skin in a case of B-Lymphoblastic Leukemia.

Juvenile xanthogranuloma is a benign self-limiting lesion commonly described in infants and young children. It most commonly involves the skin presenting as single or multiple yellowish-brown papules. Clinical scenario with the classic histomorphology showing histiocytic aggregates in the dermis with xanthomatous cytoplasm, toutan type giant cells, immunohistochemistry with positive CD68, CD163, factor XIIIa and negative CD1a and S-100 help in diagnosis. However, diagnosis becomes challenging with predominant systemic bone marrow involvement in post-B-lymphoblastic leukemia settings.

Demographics and additional haematologic cancers of patients with histiocytic/dendritic cell neoplasms.

AIMS: The discovery of somatic genetic alterations established many histiocytic disorders as haematologic neoplasms. We aimed to investigate the demographic characteristics and additional haematologic cancers of patients diagnosed with histiocytic disorders in The Netherlands. METHODS AND RESULTS: We retrieved data on histiocytosis patients from the Dutch Nationwide Pathology Databank (Palga). During 1993 to 2022, more than 4000 patients with a pathologist-assigned diagnosis of a histiocytic disorder were registered in Palga. Xanthogranulomas were the most common subtype, challenging the prevailing assumption that Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder. LCH and juvenile xanthogranuloma (JXG) had a peak incidence in the first years of life; males were overrepresented among all histiocytosis subgroups. 118 patients had a histiocytic disorder and an additional haematologic malignancy, including 107 (91%) adults at the time of histiocytosis diagnosis. In 16/118 patients, both entities had been analysed for the same genetic alteration(s). In 11 of these 16 patients, identical genetic alterations had been detected in both haematologic neoplasms. This included two patients with PAX5 p.P80R mutated B cell acute lymphoblastic leukaemia and secondary histiocytic sarcoma, further supporting that PAX5 alterations may predispose (precursor) B cells to differentiate into the myeloid lineage. All 4/11 patients with myeloid neoplasms as their additional haematologic malignancy had shared N/KRAS mutations. CONCLUSIONS: This population-based study highlights the frequency of xanthogranulomas. Furthermore, our data add to the growing evidence supporting clonal relationships between histiocytic/dendritic cell neoplasms and additional myeloid or lymphoid malignancies. Particularly adult histiocytosis patients should be carefully evaluated for the development of these associated haematologic cancers.

Atypical disseminated histiocytic sarcoma in a 7-month-old dog.

A 7-month-old intact female bearded collie dog was admitted after a 2-week history of progressive cough, inappetence, and lethargy, with no response to previous treatment with doxycycline and steroids. Mild attenuation of lung sounds in the right middle hemithorax was the only abnormality detected on physical examination. Abdominal ultrasound and thoracic radiographs were performed and revealed multifocally distributed nodules and masses, well-circumscribed and of variable size in the kidneys and pulmonary parenchyma. Ultrasound-guided fine needle aspirates of the renal and pulmonary masses were taken. A cytologic evaluation of these lesions pointed towards a malignant mesenchymal neoplasia. Euthanasia was elected due to the poor prognosis and rapid progression. The post-mortem histopathology, a positive result to IBA1 immunoperoxidase staining, and a lack of detection of infectious agents, and negative E-cadherin immunostaining enabled the final diagnosis of a disseminated histiocytic sarcoma. We report an atypical form, both in breed and age, of canine disseminated histiocytic sarcoma. While all breeds can be affected, there is a clear predisposition in some, and no cases have been previously described in bearded collies. Moreover, to the authors' knowledge, this is the youngest dog with this histiocytic disorder described to date. Disseminated histiocytic sarcoma should be considered as a differential diagnosis of multinodular tumors in dogs, regardless of the anatomic location and age of the dogs, even in puppies.

Histopathological maturation in juvenile xanthogranuloma: a blueberry muffin infant mimicking aleukemic leukemia cutis.

Juvenile xanthogranuloma (JXG) is usually identified by Touton giant cells, so their absence can complicate diagnosis. We encountered a case of non-typical neonatal JXG lacking Touton giant cells, which was difficult to differentiate from aleukemic leukemia cutis because of overlapping histopathological characteristics. A 1 month-old girl presented with a blueberry muffin rash and multiple 1-2 cm nodules within the subcutaneous and deeper soft tissues. Blood tests revealed pancytopenia. The initial nodule biopsy showed mononuclear cell infiltration, suggestive of mature monocytes or histiocytes, but no Touton giant cells. Bone marrow examination showed no evidence of leukemia. Despite worsening of the rash, pancytopenia, and weight gain over the following month, the results of the second biopsy remained consistent with the initial findings. Consequently, we provisionally diagnosed aleukemic leukemia cutis and initiated chemotherapy. After two courses of chemotherapy, the pancytopenia improved, but the nodules only partially regressed. A third biopsy of the nodule was performed to evaluate the histological response, and revealed Touton giant cells, confirming the diagnosis of JXG. In conclusion, distinguishing non-typical JXG from aleukemic leukemia cutis is challenging. This case highlights the importance of multiple biopsies and the potential for histopathological maturation.

A Case of Uncommon S100-Negative CD1a-Positive Histiocytosis in a 9-Year-Old Boy: Clinical Presentation, Histopathologic Features, and Successful Treatment Approach.

ABSTRACT: Immunohistochemically, histiocytosis differentiating into Langerhans cells is typically characterized by the expression of CD1a, S100, and varying degrees of Langerin. However, CD1a-positive but S100-negative histiocytosis is extremely rare in clinical practice. We present a case of a 9-year-old boy with multiple erythematous to brown dome-shaped nodules. Histopathologic examination revealed dermal infiltrates of histiocytic cells, exhibiting a distinctive immunohistochemical profile of CD68+, S100-, CD1a+, and Langerin-. This exceptional case may contribute to our understanding of the etiology and differentiation processes of histiocytic proliferative disorders.

Pancytopenia related to acquired sea-blue histiocytosis during chronic parenteral nutrition.

Bone marrow smear showing histiocytes (black arrow) containing sea blue granules stained with May-Grünwald Giemsa.

Antemortem cytologic diagnosis of pulmonary Langerhans cell histiocytosis in a cat.

Feline pulmonary Langerhans cell histiocytosis (FPLCH) is a rare histiocytic proliferative disease of middle-aged to older domestic cats. Langerhans cells in the terminal airways proliferate and infiltrate the interstitium and the airways to a lesser degree, widely effacing normal parenchyma. Historically, definitive diagnosis has required postmortem evaluation where pulmonary lesions have a classic gross and histologic morphology. Here, we present the first documented antemortem diagnosis of FPLCH using bronchoalveolar lavage (BAL) cytology and immunocytochemistry (ICC) in a 9-year-old British shorthair mix. The cat had a 3-month history of respiratory difficulty that was refractory to steroids and antimicrobials. Pulmonary radiographs had marked diffuse changes with a complex bronchointerstitial and micronodular pattern. BAL cytology revealed neutrophilic inflammation and markedly increased histiocytes with morphology distinct from typical pulmonary macrophages. ICC characterized histiocytes as CD1a+ /E-cadherin+ /CD11b- /PanCK- , consistent with a Langerhans cell phenotype. The cat was humanely euthanized due to poor prognosis and presented for necropsy. Gross, histopathologic, immunophenotypic, and ultrastructural findings confirmed a diagnosis of FPLCH. Proliferative cells were E-cadherin+ /Iba-1+ /CD18+ /CD1a+ /CD5+ /MHCII+ /CD204- /CD4- ; transmission electron microscopy identified the presence of Birbeck granules in the proliferating histiocytes, consistent with previous reports of FPLCH.

Primary unifocal thymic Rosai-Dorfman disease: an extremely rare challenge in diagnostic practice.

Rosai-Dorfman disease (RDD) is currently considered a group of neoplastic diseases of unknown etiology, with monoclonal proliferation of histiocytes, showing unique histopathologic features and varying clinical presentation. Primary thymic RDD is an extremely rare extranodal form of this disorder. In this study, we describe the case of an otherwise healthy 64-year-old Chinese man who presented with an isolated, asymptomatic soft tissue density lesion in the anterior mediastinum detected by computed tomography. Histology of the surgical specimen revealed infiltration of thymic tissue by sheets of large histiocytes with mixed lymphocytes and plasma cells, and background fibrosis. Immunohistochemical staining of the histiocytes was positive for S100, CD68, CD163, OCT2 and cyclin D1, but negative for CD1a and BrafV600E expression, thus supporting a diagnosis of RDD. Primary thymic RDD is extremely rare and may be a diagnostic challenge when presenting as mediastinal lesion.

Histologically atypical case of Gaucher disease type 1.

This report presents a case of childhood Gaucher disease type 1, a rare inherited metabolic disorder. Although the clinical symptoms were classical, the histological findings in this case were atypical and initially led to diagnostic uncertainty. The pathognomonic histological finding on bone marrow is Gaucher cells, which are lipid-engorged phagocytes secondary to the accumulation of glucosylceramide. These cells typically demonstrate diffuse and avid iron staining using a Prussian blue iron stain. In this case, although the histiocytes seen on bone marrow were abnormal, the absence of iron staining on bone marrow led to a large range of other diagnoses being considered. In retrospect, this anomaly was likely in the setting of prolonged iron deficiency and anaemia as a result of the insidious nature of this presentation. The prognosis of type 1 Gaucher disease is favourable, with current treatments significantly improving duration and quality of life. We explore the utility of a collaborative multidisciplinary approach in addressing diagnostic uncertainty and the importance in making a diagnosis for Gaucher disease type 1 in order to provide appropriate and targeted treatment.

Notch and retinoic acid signals regulate macrophage formation from endocardium downstream of Nkx2-5.

Hematopoietic progenitors are enriched in the endocardial cushion and contribute, in a Nkx2-5-dependent manner, to tissue macrophages required for the remodeling of cardiac valves and septa. However, little is known about the molecular mechanism of endocardial-hematopoietic transition. In the current study, we identified the regulatory network of endocardial hematopoiesis. Signal network analysis from scRNA-seq datasets revealed that genes in Notch and retinoic acid (RA) signaling are significantly downregulated in Nkx2-5-null endocardial cells. In vivo and ex vivo analyses validate that the Nkx2-5-Notch axis is essential for the generation of both hemogenic and cushion endocardial cells, and the suppression of RA signaling via Dhrs3 expression plays important roles in further differentiation into macrophages. Genetic ablation study revealed that these macrophages are essential in cardiac valve remodeling. In summary, the study demonstrates that the Nkx2-5/Notch/RA signaling plays a pivotal role in macrophage differentiation from hematopoietic progenitors.

Rosai-Dorfman disease of the breast: a clinicoradiologic and pathologic study.

Rosai-Dorfman disease (RDD) is an uncommon histiocytic disorder typically involving lymph nodes and less frequently extranodal tissues. RDD involving the breast is rare and may clinically and radiologically mimic neoplastic and non-neoplastic disorders. We report seven patients with breast RDD, describe their clinicoradiologic and pathologic features, and discuss the differential diagnosis. Patients, ranging from 15 to 74 years of age, presented with unilateral and unifocal (5/7) or bilateral and multifocal (2/7) masses. RDD was either confined to the breast (6/7) or concurrently involved a lymph node (1/7). Masses ranged from 8 to 31 mm, categorized as Breast Imaging-Reporting and Data System (BI-RADS) 4 (6/7) or 5 (1/7). All cases showed similar morphology with many large histiocytes displaying emperipolesis with associated fibrosis and dense lymphoplasmacytic infiltrate. The abnormal histiocytes co-expressed CD68/CD163, S100, OCT2, and Cyclin D1 (7/7), and were negative for CK AE1/AE3 (7/7), CD1a (7/7), and BRAF V600E (6/6). Flow cytometry (n = 3), kappa/lambda in situ hybridization (n = 5), and IgG4/IgG immunohistochemistry (n = 1) did not reveal lymphoma or IgG4-related disease. No mycobacterial or fungal organisms were identified on acid-fast bacillus (AFB) and Grocott methenamine silver (GMS) stains (n = 5). Three patients underwent complete excision and none recurred or progressed to systemic disease during follow-up (88-151 months). In summary, breast RDD should be included in the differential diagnosis of a mass-forming breast lesion. Histopathology with ancillary studies and clinicoradiologic correlation is essential for accurate diagnosis and optimal clinical management. Patients with RDD of the breast have an excellent prognosis after complete excision.

Metabolic heterogeneity of tissue-resident macrophages in homeostasis and during helminth infection.

Tissue-resident macrophage populations constitute a mosaic of phenotypes, yet how their metabolic states link to the range of phenotypes and functions in vivo is still poorly defined. Here, using high-dimensional spectral flow cytometry, we observe distinct metabolic profiles between different organs and functionally link acetyl CoA carboxylase activity to efferocytotic capacity. Additionally, differences in metabolism are evident within populations from a specific site, corresponding to relative stages of macrophage maturity. Immune perturbation with intestinal helminth infection increases alternative activation and metabolic rewiring of monocyte-derived macrophage populations, while resident TIM4+ intestinal macrophages remain immunologically and metabolically hyporesponsive. Similar metabolic signatures in alternatively-activated macrophages are seen from different tissues using additional helminth models, but to different magnitudes, indicating further tissue-specific contributions to metabolic states. Thus, our high-dimensional, flow-based metabolic analyses indicates complex metabolic heterogeneity and dynamics of tissue-resident macrophage populations at homeostasis and during helminth infection.

MUM1/IRF4 immunolabeling of neoplastic Langerhans histiocytes in a putative case of canine Langerhans cell histiocytosis.

Langerhans cell histiocytosis is a systemic histiocytic proliferative disease with cutaneous manifestations which is well described in human medical literature and has relatively recently been reclassified as a neoplastic disorder. The diagnosis of canine Langerhans cell histiocytosis has been proposed in the veterinary literature to refer to a histiocytic proliferative disease in the dog with clinical and histopathologic features that mirror the human disease. However, reports that invoke this diagnosis are rare and often lack complete diagnostic characterization. This case report presents an extensive diagnostic investigation of a putative case of Langerhans cell histiocytosis in a 3-year-old male castrated Golden Retriever dog, including gross, cytologic, histopathologic, and immunohistochemical findings. Furthermore, we document that canine LCH may have positive immunolabeling for the transcription factor multiple myeloma oncogene 1/interferon regulatory factor 4 (MUM1/IRF4), which is classically used for the diagnosis of canine plasma cell neoplasms.

Histiocytic sarcoma of the palate: a case report.

Histiocytic sarcoma is a malignant proliferation of cells that exhibit morphological and immunophenotypic features of mature histiocytes. Owing to its rarity, its clinical features and standard treatment have not yet been established. This report describes a case of histiocytic sarcoma of the palate that developed in a 76-year-old man, the first report of an intraoral histiocytic sarcoma. An extended resection was performed; however, establishing the excision line was extremely difficult because assessing the tumour boundary on imaging was challenging and the tumour underwent dynamic gross morphological changes following biopsy. Complete resection is required to obtain a favourable prognosis for high-grade tumours with indistinct borders. In this case, an intraoperative rapid examination with frozen section analysis was performed along the planned excision line to completely resect the tumours exhibiting such behaviour. At 28 months postoperatively, the patient demonstrated no recurrence or metastasis; however, he is under careful monitoring.

Cerebral manifestation and diagnostic dilemma of Rosai-Dorfman disease.

Rosai-Dorfman disease (RDD) is a rare, S100-positive histiocytic proliferation, that can cause both nodal and extranodal illness. We present a case of a 53-year-old male patient. Magnetic resonance imaging described a plaque-like meningeal lesion, and the preoperative diagnosis was meningioma. Histologically, dense infiltration of lymphocytes, plasma cells, and histiocytes was seen, furthermore, the presence of emperipolesis in the sample was pronounced. In the histiocytes nuclear and cytoplasmic positivity with S100 protein, and nuclear positivity with Cyclin D1 was observed. The case was concluded as RDD. Morphological appearance of intracranial RDD with imaging procedures can present a differential diagnostic challenge. The correct diagnosis is based on the presence of histiocytes with emperipolesis, and properly defined immunohistochemical characteristics.