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1. Emperipolesis , Entosis , Cell Cannibalism : Demystifying the cloud Dr Palak Borade Post Graduate Trainee

2. 2 Title : Emperipolesis , Entosis , Cell Cannibalism : Demystifying the cloud Volume : Volume 21 | Issue 1 | January ‑ April 2017 journal : Journal of Oral and Maxillofacial Pathology Author : Dr Nidhi Gupta, Dr Kiran Jadhav, Dr Vandana Shah

3. Contents : About the article 1 Introduction : cell in cell structure 2 History of CIC 3 3 Concluding Remarks Detailed cell in cell structure characterization Merits & Demerits 5 4 6

4. About the Article: A gap of knowledge was found in concept designing and clarity about understanding of aforementioned terminologies. These are closely related phenomena with a very fine line of differences . Its correct identification has a significant diagnostic and prognostic value The various cell engulfment phenomena are very similar looking but operate through entirely different pathways 4

5. Introduction : 5  The internalization of one cell by another is most commonly associated with the phagocytic engulfment of apoptotic cells. However, alternative mechanisms of cell internalization also target viable cells for internalization, forming what are referred to as cell-in-cell structures . Cell-in-cell structures can form between various host and target cell types. Internalized cells within cell-in-cell structures remain viable for extended periods of time and exhibit various possible fates.

6. Cell in cell structure : . 6 HETEROTYPIC (Emperipolesis ) HOMOTYPIC: ( Entosis ) Phagocytosis like – Cell Cannibalism

7. History of CIC: 7 CIC was originally described in the second half of the 19th century Karl J. Eberth reported lymphocytes inside intestinal epithelial cells Steinhaus described the first homotypic CIC structures arising between cancer cells von Leyden introduced the term “cell cannibalism” in 1904 In 1925 , Lewis observed homotypic CIC structures formed by white blood cells 1956 , Humble described the “active penetration of one cell by another which remains intact”, using the term “ emperipolesis ”

8. Cellular Cannibalism 8 The word cannibalism is derived from cannibals which is the Spanish name for the Carib people formerly well known for practicing cannibalism – practice of humans eating the flesh or internal organs of other human beings. Leyden used the term, “ birds” eye cells for cells exhibiting this phenomenon. Other terms are “ cellular phagocytosis,” “cell phagocytosis,” “cell–in‑cell appearance,” “cell‑in‑cell pattern,” “ one cell delicately wrapped around the next,” “tumor cell within a tumor cell ,”

9. Introduction to cellular cannibalism 9 Cellular cannibalism is defined as the ability of a cell to engulf another living cell leading eventually to the death of the internalized cell. It is considered as a sort of “ feeding ” activity aimed at sustaining survival and progression of malignant tumor cells in an unfavorable condition .

10. 10 Cellular cannibalism Self cannibalism xenocannibalism Self repair digested to death Can engulf homotypic or heterotypic cell

11. Occurrence : 11 The earliest report of a cell–in‑cell phenomenon in tumors was reported by Steinhans in 1891. The engulfed cell still remains alive when internalized, but the process implies its death . cancer cannibalism has been used to differentiate between benign tumors from malignant, but few studies recently have reported its occurrence in giant cell tumor of tendon sheath and central and peripheral giant cell granuloma ( PGCG ) of the oral cavity. In cannibalism, the tumor cells are seen engulfing cells such as other tumor cells, neutrophils and erythrocytes .

12. Histopathology : 12 CC in cytological or histological preparation is manifested as a cell that is contained within another bigger cell with a crescent shaped nucleus . This particular appearance is attributed to the fact that ingested cell is contained in a big vacuole that pushes the nucleus of cannibalistic cell to the periphery . Vol. 37, No. 4  :  REVIEWS An overview on “cellular cannibalism” with special reference to oral squamous cell carcinoma Jain M.

13. 13 Cellular Cannibalism Alka Kale Professor of Oral Pathology and Microbiology Principal, KLE VK Institute of Dental Sciences Dean, Faculty of Dentistry KLE University, Belagavi - 590 010, India

14. Pathogenesis : 14

15. Mechanism : 15 Krajcovic Et Al. Cannibalistic Cell Engulfment Polyploidy Internalized Cells Disrupt Promote Tumor Progression Aneuploidy Aggressive behaviour of cancer

16. 16 At times, a malignant cell which has engulfed another malignant cell might, in turn, get engulfed by a third malignant cell. The process is referred to as complex cannibalism Cannibalistic giant cells as well as stromal cells express histiocytic markers. The internalized cells do not express bcl2, suggesting that this internalization induces apoptotic cell death

17. Factors Regulating It : Hunger of tumor cells 17 Tumor microenvironment Dynamic link between caveolin1, actin cytoskeleton and ezrin.

18. Need of an hour : 18 The hidden state holds great possibility of the escape of tumor cells from host immune system ( immune escape). The number of cannibalistic cells directly correlates with the poor prognosis of the tumor. Cannibalistic cells are thus well related to aggressive behavior, anaplasia, invasiveness and metastatic potential of the malignancy. This opens a new arena of research to definitely target such cells in tumor immunotherapy.

19. EMPERIPOLESIS 19 Emperipolesis is a condition, wherein hematopoietic cells in living and intact state are seen in the cytoplasm of host cell without any damage The term was first described by   Humble et al. in 1956 as, “the active penetration of one cell by another which remains intact

20. The cells taken in frequently are neutrophils, lymphocytes and plasma cells . The host cells may be a megakaryocyte, monocyte, endothelial cell, fibroblast and a malignant cell. Emperipolesis has been detected in bone marrow aspirates, tissue cultures, cerebrospinal fluid (CSF), fine‑needle aspiration cytology (FNAC) and imprint cytology. It has been more commonly seen in non‑Hodgkin’s lymphoma than in Hodgkin’s lymphoma 20 Introduction to Emperipolesis

21. The fate of cells involved in emperipolesis can vary. In some circumstances, both cells remain viable and thus the inner cell escapes from the host cell. This observation gave rise to the term “ emperipolesis ”, which means “ wandering around within ” and reflects the inner cell’s journey into another cell , through its cytoplasm, and outside Emperipolesis can affect both the inner and outer cell . The inner cell can undergo mitosis as well as die via different pathways ( apoptosis, necrosis ) The outer cell can remain intact or be killed in the process ( actively by granzyme B ) 21

22. Histopathology : 22 In emperipolesis, the engulfed cell is enclosed in a membrane‑bound vacuole in the cytoplasm of host cell. This gives a rim of clear halo around the engulfed cell Sometimes, vacuolations are also seen in the cytoplasm. On occasion, internalized cells appear to continue living within the host cell for brief periods of time following the engulfment, sometimes even dividing within the vacuole, in which they are housed Some internalized cells manage to escape from the host cell and survive to continue life as an individual cell.

23. Pathogenesis : 23 Since the term “emperipolesis” was coined, several attempts have been made to understand how a cell inhabits the other , and the biological relevance of this co-habitation with their final respective fates. Emperipolesis is now understood as a mechanism to improve cell survival and help prevent apoptosis of cells within the host cell or control cells that could be cytotoxic to the host cells. Wang and Li attempted to propose the mechanism behind emperipolesis. They described this as a mechanism of the natural killer cell to mediate tumor cell death.

24. 24 Emperipolesis

25. Emperipolesis is the hallmark of rosai – dorfman disease (RDD), A non-malignant disorder in which histiocytes infiltrate lymph nodes and other tissue Emperipolesis might be its role in viral transmission. The prevalence of emperipolesis in rdd might be useful in distinguishing the disease from clinically similar conditions Despite extensive studies on emperipolesis, the process is still not fully understood. Its function and clinical effects are debatable, mostly due to its ambiguous possible outcomes on the cellular level. Factors determining the course of emperipolesis remain mostly unknown . 25 Classification of Cell-in-Cell Structures: Different Phenomena with Similar Appearance Karol Borensztejn 1,†, Paweł Tyrna 1,†, Agata M. Gaweł 1 , Ireneusz Dziuba 2,3 , Cezary Wojcik 4,‡ , Lukasz P. Bialy 5 and Izabela Mlynarczuk -Bialy

26. Entosis : 26 Overholtzer et al. observed a homogeneous cell‑in‑cell phenomenon similar to emperipolesis and gave the term “ entosis ” to it (from the Greek word “ entos ” for “inside” or “into”).

27. A cell engulfs a cell of same type. This was proposed as a process of cell‑in‑cell invasion , which plays a physiological role in the elimination of cells detached from a surface 27

28. Pathogenesis : 28

29. Entotic cell engulfment is induced by detachment of a cell from the extracellular matrices and further potentiated by imbalances in actomyosin contraction between the neighboring cells. Entosis is driven by imbalances in actomyosin contraction between the neighboring cells. This similar cell–to‑cell engulfment is mediated by adherens junction molecules such as E‑cadherins, Rho GTPase and Rho‑kinase (ROCK)‑ mediated actomyosin contraction within engulfing cells. There is absence of integrin signaling and force‑driven invasion of one cell into another cell. Cell engulfment requires actin, myosin II, Rho and ROCK activity of the invading cell and myosin‑based contractile force from the recipient cell 29

30. Entosis lysosomal cell death invading cells try to escape through a transcytosis‑like movement cells undergo cell division within the host cells. Stimulation of entosis by oncogene kras , as one class of tumor suppressors. regulation of epithelial cadherins e and p. oncogenic transformation in a cell leads to its capability to engulf the other cells physical elimination of the “ loser ” cells, which usually succumb to nonapoptotic cell death This phagosome has membrane surface lc3 which then fuses with lysosomes . 30

31. 31

32. Merits & Demerits : Merits: CIC remains poorly understood but the author described in all three phenomenon in one article Histopathology and pathogenesis was well explained Demerits : Relationship between CICS and cancer wasn’t talked about Cancer type and its distribution in primary lesion and metastases wasn’t talked about CICs in physiology and pathology wasn’t explained 32

33. Concluding Remarks : 33 The process of emperipolesis, entosis and cannibalism is a very similar‑appearing phenomenon but primarily differs in the patterns of operation and mechanisms involved. They provide a fascinating platform to study cell–in‑cell interaction. As entosis and cannibalism are common findings in many tumors, further studies in relation to use in cancer diagnosis and prognosis would help us solve the hidden mystery behind the immunosurveillance exhibited by cancer. As these are easily identifiable morphological features under light microscopy, tumor aggressiveness can be routinely assessed, avoiding the use of expensive molecular techniques.

34. 34 Stuart AE. Phagocytic engulfment and cell adhesiveness as cellular surface phenomena. J Clin Pathol 1977;30:592. Jef A. It’s a Cell‑Eat‑Cell World. In The Scientist. Exploring life Inspiring Innovation. Available from: http://www.the‑scientist. com/? articles.view / articleNo /30956/title/It‑s‑a‑Cell‑Eat‑Cell‑World/. [Last updated on 2011 Aug 01; Last assessed on 2015 Dec 25]. Amita K, Vijay Shankar S, Abhishekh MG, Geethalakshmi U. Emperipolesis in a case of adult T cell lymphoblastic lymphoma (mediastinal type) – Detected at FNAC and imprint cytology. Online J Health Allied Sci 2011;10:11. Raja H, Subramanyam SG, Govindaraj S, Babu MK. A rare cause of massive lymphadenopathy. Indian J Surg Oncol 2011;2:212‑4. Sable MN, Sehgal K, Gadage VS, Subramanian PG, Gujral S. Megakaryocytic emperipolesis: A histological finding in myelodysplastic syndrome. Indian J Pathol Microbiol 2009;52:599‑600. Janssen CE, Rose CD, Naranjo A, Meunier BB, Cimaz R, Harjacek M, et al. Emperipolesis and cell death in NOD2‑related Blau syndrome and Crohn’s disease. Pediatr Rheumatol Online J 2011;9 Suppl 1:P293. Lewis WH. The engulfment of living blood cells by others of the References :