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.

Coexistence of Rosai-Dorfman disease and Hodgkin's lymphoma in a patient with cervical lymphadenopathy.

A man in his 40s, with no tobacco or alcohol habit, was referred to the otorhinolaryngology department presenting with a 2-month history of enlarged left cervical lymphadenopathy with no other signs or symptoms. The ear, nose and throat examination showed no abnormalities apart from the described lymphadenopathy. An ultrasound scan suggested these nodes to be part of either an inflammatory or a malignant process. Subsequent positron emission tomography-CT proved those lymph nodes to be metabolically active, as well as others within the thorax. Cervicotomy was performed and the histopathological analysis showed dilated sinuses and histiocytes with emperipolesis. Suspecting Rosai-Dorfman disease (RDD), high-dose steroid therapy was started; but given no improvement was observed, a second cervicotomy was performed, with the histopathological diagnosis of the latter of Hodgkin's lymphoma. The present article aims to emphasise the need to exclude haematological disorders whenever RDD histology is observed, given their possible coexistence, and a worse outcome and clinical and histopathological semblance.

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.

Lymphocytic emperipolesis in breast carcinoma on cytology smears-A curious finding!

In this article, we discuss an intimidating finding of lymphocytic emperipolesis which was observed in breast carcinoma cells on cytology smears.

Inhibition of CXCR1/2 reduces the emperipolesis between neutrophils and megakaryocytes in the Gata1low model of myelofibrosis.

Emperipolesis between neutrophils and megakaryocytes was first identified by transmission electron microscopy. Although rare under steady-state conditions, its frequency greatly increases in myelofibrosis, the most severe of myeloproliferative neoplasms, in which it is believed to contribute to increasing the transforming growth factor (TGF)-ß microenvironmental bioavailability responsible for fibrosis. To date, the challenge of performing studies by transmission electron microscopy has hampered the study of factors that drive the pathological emperipolesis observed in myelofibrosis. We established a user-friendly confocal microscopy method that detects emperipolesis by staining with CD42b, specifically expressed on megakaryocytes, coupled with antibodies that recognize the neutrophils (Ly6b or neutrophil elastase antibody). With such an approach, we first confirmed that the bone marrow from patients with myelofibrosis and from Gata1low mice, a model of myelofibrosis, contains great numbers of neutrophils and megakaryocytes in emperipolesis. Both in patients and Gata1low mice, the emperipolesed megakaryocytes were surrounded by high numbers of neutrophils, suggesting that neutrophil chemotaxis precedes the actual emperipolesis event. Because neutrophil chemotaxis is driven by CXCL1, the murine equivalent of human interleukin 8 that is expressed at high levels by malignant megakaryocytes, we tested the hypothesis that neutrophil/megakaryocyte emperipolesis could be reduced by reparixin, an inhibitor of CXCR1/CXCR2. Indeed, the treatment greatly reduced both neutrophil chemotaxis and their emperipolesis with the megakaryocytes in treated mice. Because treatment with reparixin was previously reported to reduce both TGF-ß content and marrow fibrosis, these results identify neutrophil/megakaryocyte emperipolesis as the cellular interaction that links interleukin 8 to TGF-ß abnormalities in the pathobiology of marrow fibrosis.

Strong Coexpression of Transcription Factors PU.1 and Oct-2 in Rosai-Dorfman Disease.

OBJECTIVES: Rosai-Dorfman disease (RDD) is a rare disorder characterized by the accumulation of large S100 protein-positive histiocytes that typically exhibit emperipolesis. The recently reported expression of Oct-2 in RDD histiocytes led us to explore whether PU.1, a transcription factor that is required for monocyte and B-cell development, could similarly function as a diagnostic marker in RDD. METHODS: We evaluated the expression of PU.1 and Oct-2 using immunohistochemistry in 19 patients diagnosed with RDD involving nodal, extranodal, and cutaneous sites. RESULTS: Both PU.1 and Oct-2 were positive in all cases studied, with a strong intensity of staining in 84% of cases in which more than 50% of the lesional cells were positive. In three patients, both markers showed weak to moderate intensity of staining. Two patients had concomitant RDD and Langerhans cell histiocytosis in which PU.1 stained both types of histiocytes while Oct-2 stained only the RDD component. CONCLUSIONS: PU.1 emerged as a robust marker with crisp nuclear staining in RDD histiocytes as well as in engulfed inflammatory cells. Strong coexpression of PU.1 and Oct-2 is a useful diagnostic marker in differentiating histiocytic/dendritic cell proliferations.

Rosai Dorfman's disease of the maxillary bone with soft tissue involvement of the cheek: Case Presentation and Literature Review / Enfermedad de Rosai Dorfman de maxilar con compromiso de partes blandas de mejilla: Presentación de caso y revisión de la literatura

The Rosai-Dorfman disease (RDD) is a bening entity, of unknown etiology, rare, characterized by the overproduction of histiocytes and their subsequent accumulation in the lymph nodes, which may also compromise other organs and systems. It predominantly affects young people. The histological study, which shows emperipolesis, is very indicative but not pathognomonic, but with the immunohistochemistry the diagnosis of the disease is reached, which does not have a well-protocolized treatment. Its evolution is highly variable, with spontaneous remission being a possibility, although in some cases the commitment is extensive, compromising important or vital anatomical structures that requiere vigorous treatment, which can be surgical, radiotherapy and even chemotherapy. We present a case of RDD that affected a 17-year-old girl with upper jaw and right maxillary sinus commitment, which began with loss of teeth, and subsequent appearance of a painless and deforming facial tumour that underwent surgical resection. In this case, the etiological diagnosis was not posible in the preoperative period despite multiple biopsies. An extensive review of the literature is carried out in order to a better understanding of this pathology.

La Enfermedad de Rosai-Dorfman (ERD) es una entidad benigna, de etiología desconocida, poco frecuente, caracterizada por la sobreproducción de histiocitos y su posterior acúmulo en los linfonodos, pudiendo comprometer también a otros órganos y sistemas. Afecta predominantemente a personas jóvenes. El estudio histológico, que muestra emperipolesis, es muy orientativa pero no patognomónica, aunque con la Inmunohistoquímica se llega al diagnóstico de la enfermedad que no tiene un tratamiento bien protocolizado. Su evolución es muy variable, siendo la remisión espontánea una posibilidad, no obstante, en algunos casos, el compromiso es extenso, comprometiendo estructuras anatómicas importantes o vitales que requieren de un tratamiento enérgico, pudiendo ser éste quirúrgico, radioterápico y aún quimioterápico. Se presenta un caso de ERD que afectó a una joven de 17 años, con compromiso de maxilar y seno maxilar derecho, que debutó con pérdida de piezas dentarias y posterior aparición de un tumor facial indoloro y deformante que fue sometido a resección quirúrgica. En este caso no fue posible el diagnóstico etiológico en el preoperatorio pese a múltiples biopsias. Se hace una extensa revisión de la literatura con el objeto de conocer mejor esta patología.

Neutrophil transit time and localization within the megakaryocyte define morphologically distinct forms of emperipolesis.

Neutrophils transit through megakaryocytes in a process termed emperipolesis, but it is unknown whether this interaction is a single type of cell-in-cell interaction or a set of distinct processes. Using a murine in vitro model, we characterized emperipolesis by live-cell spinning disk microscopy and electron microscopy. Approximately half of neutrophils exited the megakaryocyte rapidly, typically in 10 minutes or less, displaying ameboid morphology as they passed through the host cell (fast emperipolesis). The remaining neutrophils assumed a sessile morphology, most remaining within the megakaryocyte for at least 60 minutes (slow emperipolesis). These neutrophils typically localized near the megakaryocyte nucleus. By ultrastructural assessment, all internalized neutrophils remained morphologically intact. Most neutrophils resided within emperisomes, but some could be visualized exiting the emperisome to enter the cell cytoplasm. Neutrophils in the cytoplasm assumed close contact with the platelet-forming demarcation membrane system or the perinuclear endoplasmic reticulum. These findings reveal that megakaryocyte emperipolesis reflects at least 2 distinct processes differing in transit time and morphology, fast and slow emperipolesis, suggesting divergent physiologic functions.

Fumarate hydratase-deficient renal cell carcinoma: A tumor with diverse morphology including cannibalism, lymphocytic emperipolesis, and defective autophagy.

We report the clinicopathological findings of the first series of 3 patients from Brazil with fumarate hydratase-deficient renal cell carcinoma. The clinicopathological findings disclosed a very aggressive tumor. All 3 patients had solitary tumor at the left side, metastasis and advanced stage at the time of diagnosis; were females with a median age of 40 years; had a history of uterine leiomyomas; and, at follow-up two patients are deceased and one patient alive. The microscopic findings of these 3 patients are in accordance with the literature disclosing a variety of morphologic features being papillary arrangement, eosinophilic cytoplasm, and prominent nucleoli surrounded by clear halo the constant and most frequent findings. Previously not reported in this tumor, we describe presence of cannibalism, lymphocytic emperipolesis, and cytoplasmic vacuoles with eosinophilic inclusions associated with overexpression of p62 in immunohistochemistry which is considered to be evidence of defective autophagy. Lymphocytic emperipolesis was a more frequent finding than cannibalism and immunohistochemistry for p62 was overexpressed only in the 2 patients disclosing cytoplasmic vacuoles with eosinophilic inclusions. The presence, frequency and significance of these novel findings should be checked in large series of this rare and aggressive tumor aiming to associate with clinical behavior and eventually influence the strategy of treatment.

Rosai-Dorfman Disease of Bone and Soft Tissue.

CONTEXT.­: Rosai-Dorfman disease is a rare histiocytic proliferative disorder of unknown pathogenesis that may be diagnostically difficult in extranodal sites. It is commonly an unsuspected diagnosis when arising in bone and soft tissue, especially when it presents without associated lymphadenopathy. Its variable clinical presentation and nonspecific imaging findings make the diagnosis quite challenging, particularly in small biopsies. The problem is compounded by its less-characteristic histomorphologic features in comparison with nodal disease. Awareness of the potential diagnostic pitfalls in Rosai-Dorfman disease of bone and soft tissue should raise the degree of diagnostic accuracy. OBJECTIVE.­: To review the clinical manifestations, imaging characteristics, and histomorphologic features of Rosai-Dorfman disease of bone and soft tissue along with a brief discussion of its differential diagnosis, pathogenesis, and current management. DATA SOURCES.­: Thorough review of the literature with focus on clinical manifestations, imaging findings, key histomorphologic features, pathogenesis, and treatment. CONCLUSIONS.­: The diagnosis of Rosai-Dorfman disease of bone and soft tissue may be quite challenging because of its variable clinical presentation and nonspecific imaging findings. It may be asymptomatic without systemic manifestations or associated lymphadenopathy. The definitive diagnosis relies on histopathologic identification of the characteristic S-100-positive histiocytes demonstrating emperipolesis. Bone and soft tissue lesions tend to have lower numbers of characteristic histiocytes and less conspicuous emperipolesis and often demonstrate areas of fibrosis or storiform spindle cell areas resembling fibrohistiocytic lesions. Awareness of these unusual features is necessary in order to consider Rosai-Dorfman disease in the differential diagnosis when confronting these rare and often misleading lesions.

Classification of Cell-in-Cell Structures: Different Phenomena with Similar Appearance.

A phenomenon known for over 100 years named "cell-in-cell" (CIC) is now undergoing its renaissance, mostly due to modern cell visualization techniques. It is no longer an esoteric process studied by a few cell biologists, as there is increasing evidence that CICs may have prognostic and diagnostic value for cancer patients. There are many unresolved questions stemming from the difficulties in studying CICs and the limitations of current molecular techniques. CIC formation involves a dynamic interaction between an outer or engulfing cell and an inner or engulfed cell, which can be of the same (homotypic) or different kind (heterotypic). Either one of those cells appears to be able to initiate this process, which involves signaling through cell-cell adhesion, followed by cytoskeleton activation, leading to the deformation of the cellular membrane and movements of both cells that subsequently result in CICs. This review focuses on the distinction of five known forms of CIC (cell cannibalism, phagoptosis, enclysis, entosis, and emperipolesis), their unique features, characteristics, and underlying molecular mechanisms.

Cutaneous Rosai-Dorfman disease: a challenging diagnosis.

Rosai-Dorfman disease is a rare benign histiocytic proliferative disease of unknown cause that, in exceptional cases, presents with lesions confined to the skin. Clinically variable types of lesions such as papules, nodules and plaques have been reported. We present a case of a 27-year-old woman with a 1-year history of erythematous papular and nodular lesions on the malar and right axillary regions, previously misdiagnosed as acne. She reported no fever, malaise or weight loss, while physical examination and laboratory workup were normal. Bacteriological and mycobacteriological cultures were negative. Histopathological findings showed dense infiltration of inflammatory cells involving the entire dermis, consisting of large macrophages with emperipolesis, S100 and CD68 positive, neutrophils, eosinophils, lymphocytes and plasma cells. The patient was treated with oral prednisolone without improvement. Dapsone was subsequently initiated with favourable clinical response. The present article aimed to emphasise the clinical and histological differential diagnosis and share the treatment experience.

Biphasic Squamoid Alveolar Renal Cell Carcinoma of the Kidney Involved by Atypical CD5-Positive B-Cells.

Biphasic squamoid alveolar renal cell carcinoma (BSARCC) is a recently described kidney cancer entity with <60 published cases so far. Some unique features of BSARCC include distinct squamoid and alveolar morphology forming glomeruloid configurations and 2 types of tumor cells with different immunoprofiles. Although the mechanism is unknown, neutrophils and cellular materials engulfed by larger tumor cells (described as "emperipolesis") are observed in all reported cases including the current one. In this article, we report a case of a 70-year-old man who presented with an incidental renal mass during workup for immunoglobulin M monoclonal gammopathy of unknown significance and cold agglutinin autoimmune hemolytic anemia. A detailed pathologic evaluation and immunohistochemical studies revealed BSARCC colliding with atypical CD5+ monoclonal B-cells.