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.

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.

Emperipolesis of lymphocytes by mesothelial cells in pleural effusion involved by T-lymphoblastic lymphoma.

Emperipolesis is a physiologic or pathologic phenomenon characterized by the presence of intact viable cells within the cytoplasm of another cell. It has been described in normal tissues and in a variety of inflammatory and neoplastic lesions such as Rosai-Dorfman disease, tumors, hematopoietic disorders and rarely lymphomas. Emperipolesis by mesothelial cells is rare. Few cases of mesothelial emperipolesis of neoplastic lymphocytes in pleural effusions involved by lymphomas have been reported in the literature. Its etiopathogenesis and significance are controversial and speculative. We report a case of a 36-year-old man who presented with cough, chest pain, breathing difficulty, pericardial, and bilateral pleural effusions secondary to mediastinal T-lymphoblastic lymphoma. Pleural fluid cytology slides and cell block sections showed numerous single dispersed neoplastic lymphoblasts with occasional giant multinucleated mesothelial cells with emperipolesis of lymphocytes. The background showed scattered and clumped apoptotic karyorrhexis debris and reactive mesothelial cells. Cell block immunohistochemistry showed CD3, CD5, CD7, CD10, CD99, and TdT positive lymphocytes, consistent with involvement by T-lymphoblastic lymphoma. The giant cells were positive for cytokeratin, calretinin and WT1 confirming their mesothelial origin. Lymphoid effusions with emperipolesis may raise a potential diagnostic pitfall because they may morphologically be confused with other inflammatory and neoplastic lesions. This cell-in-cell phenomenon can be a helpful clue in the differential diagnosis of lymphocyte-rich effusions since it has been described in association with lymphomas. It might shed some light on the lymphocyte-mesothelial interaction and the potential phagocytic antigen-presenting properties of mesothelial cells under certain circumstances.

Cell-in-Cell Structures in the Liver: A Tale of Four E's.

The liver is our largest internal organ and it plays major roles in drug detoxification and immunity, where the ingestion of extracellular material through phagocytosis is a critical pathway. Phagocytosis is the deliberate endocytosis of large particles, microbes, dead cells or cell debris and can lead to cell-in-cell structures. Various types of cell endocytosis have been recently described for hepatic epithelia (hepatocytes), which are non-professional phagocytes. Given that up to 80% of the liver comprises hepatocytes, the biological impact of cell-in-cell structures in the liver can have profound effects in liver regeneration, inflammation and cancer. This review brings together the latest reports on four types of endocytosis in the liver -efferocytosis, entosis, emperipolesis and enclysis, with a focus on hepatocyte biology.

Enfermedad de Rosai-Dorfman en mama de paciente masculino: una entidad rara / Rosai-Dorfman disease of the breast in a male patient: A rare entity

La enfermedad de Rosai-Dorfman es una entidad rara que afecta al tejido linfático. Hasta un 43% de los casos pueden tener afección extranodal. La etiología se desconoce; se ha propuesto que es una disfunción inmune. Se caracteriza por la dilatación de los sinusoides linfáticos, ocasionada por un aumento en el número de histiocitos, que van acompañados por múltiples células plasmáticas. En el citoplasma de los histiocitos se encuentran células inflamatorias: fenómeno conocido como «emperipolesis». Se presenta el caso de un paciente varón, quien acude por tumoración en mama derecha. Los estudios confirmaron la enfermedad de Rosai-Dorfman. Se realizó el diagnóstico por biopsia y estudio de anatomía patológica. Se concluyó que esta afección puede confundirse con cáncer de mama. El interés que tiene la presentación de este caso es debido a la escasa frecuencia de esta enfermedad en tejido mamario de pacientes masculinos

Rosai-Dorfman disease is a rare entity that affects the lymphatic tissue; up to 43% of cases may have extranodal involvement. The aetiology is unknown but immune dysfunction has been suggested. This disease is characterised by dilation of the lymphatic sinusoids, caused by an increase in the number of histiocytes, which are accompanied by multiple plasma cells. Inflammatory cells are found in the cytoplasm of the histiocytes, a phenomenon known as «emperipolesis». We present the case of a male patient who presented with a tumour in the right breast. Studies confirmed Rosai-Dorfman disease. The diagnosis was made by biopsy and pathological analysis. This condition may be confused with breast cancer. The interest of this case lies in the low frequency of this entity in the breast tissue of male patients

Suicidal emperipolesis: a process leading to cell-in-cell structures, T cell clearance and immune homeostasis.

"Suicidal emperipolesis" is one of the most recently reported processes leading to cell-in-cell structures that promote cell death. This process was discovered in studies investigating the fate of autoreactive CD8 T cells activated within the liver. Recently, we reported that activated T cells invaded hepatocytes, formed transient cell-in-cell structures, and were rapidly degraded within endosomal/lysosomal compartments by a non-apoptotic pathway. Importantly, pharmacological inhibition of this process caused intrahepatic accumulation of tissue-reactive T cells and breach of immune tolerance. The characterization of the molecular mechanisms of suicidal emperipolesis is still in its infancy, but initial studies suggest this phenomenon is distinct from other reported cell-in-cell structures. As opposed to the formation of other cell-in-cell structures, suicidal emperipolesis takes place in a non-malignant environment, and without obvious pathology. It is therefore the first cell-in-cell structure described to have a role in maintaining homeostasis in normal physiology in higher organisms. T cell emperipolesis within hepatocytes has also been observed by pathologists in a range of chronic human liver pathologies. As T cell-in-hepatocyte structures resulting from suicidal emperipolesis are very transiently observed in normal physiology, their accumulation during liver disease would suggest that severe tissue injury is promoted by, or associated with, defective T cell clearance. In this review, we compare "suicidal emperipolesis" to other processes leading to cell-in-cell structures, and consider its potential biological roles in maintaining immune homeostasis and tolerance in the context of the hepatic environment.

Entosis and Related Forms of Cell Death within Cells.

By eliminating the unneeded or mutant cells, programmed cell death actively participates in a wide range of biological processes from embryonic development to homeostasis maintenance in adult. Continuing efforts have identified multiple cell death pathways, with apoptosis, necrosis and autophage the mostly studied. Recently a unique cell death pathway called "cell-in-cell death" has been defined. Unlike traditional cell death pathways, cell-in-cell death, characterized by cell death within another cell, is triggered by the invasion of one cell into its neighbor and executed by either lysosome-dependent degradation or caspase-dependent apoptosis. With remarkable progresses on cell-in-cell over past few years, multiple mechanisms, including entosis, cannibalism and emperitosis, are found to be responsible for cell-in-cell death. Some key questions, such as specific biochemical markers to distinguish precisely the properties of different cell-in-cell structures and the physiological and pathological relevance, remain to be addressed. In light of this situation and a surge of interests, leading scientists in this field intend to share with readers current research progresses on cell-in-cell structures from different model systems through this special edition on cell-in-cell. The mechanistic advances will be highlighted while the future researches be speculated.

[Erdheim-Chester disease and Rosai-Dorfman disease: Pathological, radiological and clinical features of adult non-Langerhans cell histiocytosis]. / Erdheim-Chester- und Rosai-Dorfman-Erkrankung : Klinisch-radiologisch-pathologische Diagnostik von Non-Langerhans-Zell-Histiozytosen des Erwachsenenalters.

Non-Langerhans cell histiocytoses (N-LCH) of adulthood are rare disorders with heterogeneous pathogenesis, morphology and clinical presentation. In this review two disorders are presented, which predominantly develop in extracutaneous sites in adults. Erdheim-Chester disease is a rare nonhereditary clonal disorder of lipid storing histiocytes most commonly presenting as osseous involvement of the long bones. Other organ manifestations include the central nervous system (CNS), the cardiovascular system, the retroperitoneum and kidneys and less commonly the skin and the lungs. Immunohistochemical staining reveals positivity for the macrophage markers CD163, CD68 and lysozyme but CD1a and langerin are negative, in contrast to Langerhans cell histiocytosis. Rosai-Dorfman disease is considered to be a reactive histiocytic proliferation occurring mainly in lymph nodes. Prominent sinuses filled with commonly multinucleated, S100-positive histiocytes with emperipolesis are a characteristic feature and develops particularly as extensive lymphadenopathy with massive sinus histiocytosis but can also occur extranodally. Painless bilateral cervical lymph node enlargement is the most common clinical presentation. This review summarizes the clinical, radiological and histopathological findings and discusses the recent molecular advances in these rare disorders.

Neutrophil-tumor cell phagocytosis (cannibalism) in human tumors: an update and literature review.

The recognition and removal of apoptotic cells by tissue macrophages and nonprofessional phagocytes, in a process called efferocytosis, is critical for development, tissue homeostasis and resolution of inflammation. Apoptotic bodies arising in tumor tissue are ingested by viable neoplastic cells and by resident macrophages. We described tumor cell phagocytosis of apoptotic neutrophils in human gastric carcinomas. This phenomenon is analogous to neutrophil efferocytosis performed by macrophages and by nonprofessional phagocytes during inflammatory reaction but is distinct by other types of cell-in-cell phenomena including emperipolesis and entosis both cytologically and biologically. In this review, we discussed them in their ultrastructural morphology, physiological roles, and clinicopathologic implications. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".

Emperipolesis: an additional common histopathologic finding in H syndrome and Rosai-Dorfman disease.

H syndrome is a recently described autosomal recessive disorder characterized by indurated, hyperpigmented, and hypertrichotic cutaneous plaques, mainly involving the lower abdomen and lower extremities. Associated systemic manifestations include hepatosplenomegaly, heart anomalies, hearing loss, hypogonadism, low height, and hyperglycemia. H syndrome is caused by mutations in the gene SLC29A3, which encodes hENT3, a member of the human equilibrative nucleoside transporter family. Histopathologically, cutaneous lesions of H syndrome consist of dermal and subcutaneous fibrosis with inflammatory infiltrate mostly composed of large histiocytes, some plasma cells, and scattered lymphoid aggregates. Recently, histopathologic and immunohistochemical studies have demonstrated that the immunophenotype of the histiocytes infiltrating the skin of a patient with H syndrome is similar to that of the lesions of Rosai-Dorfman disease. Furthermore, mutations in SLC29A3 gene have also been demonstrated in patients described as having an inherited form of Rosai-Dorfman disease, named Faisalabad histiocytosis or familial Rosai-Dorfman disease. We describe emperipolesis in the cutaneous lesions of a patient with H syndrome, further supporting the relationship between Rosai-Dorfman disease and H syndrome.

Progress of research in cell-in-cell phenomena.

The discovery of a nonphagocytotic process of cell-in-cell phenomena can be traced to over a century ago. However, its biological significance remains poorly understood. Three types of cell-in-cell phenomena have been described so far, termed "cannibalism," "emperipolesis," and "entosis." These three kinds of cell-in-cell phenomena, apart from a common feature of one cell internal to another, are distinct both cytologically and biologically. In this review, we discussed them in their morphology, cell recognition, penetration mechanisms, and physiological roles, respectively.