{"paper_id":"8f0bf85a-b0ef-4ce7-9c6c-b44e39d35228","body_text":"R E V I E W Open Access\nExtrapelvic endometriosis: a rare entity or an\nunder diagnosed condition?\nNikolaos Machairiotis 1, Aikaterini Stylianaki 2, Georgios Dryllis 3, Paul Zarogoulidis 4*, Paraskevi Kouroutou 5,\nNikolaos Tsiamis 1, Nikolaos Katsikogiannis 6, Eirini Sarika 6, Nikolaos Courcoutsakis 7, Theodora Tsiouda 8,\nAndreas Gschwendtner 9, Konstantinos Zarogoulidis 4, Leonidas Sakkas 10, Aggeliki Baliaka 10\nand Christodoulos Machairiotis 1\nAbstract\nEndometriosis is a clinical entity characterized by the presence of normal endometrial mucosa abnormally\nimplanted in locations other than the uterine cavity. Endometriosis can be either endopelvic or\nextrapelvicdepending on the location of endometrial tissue implantation. Despite the rarity of extrapelvic\nendometriosis, several cases of endometriosis of the gastrointestinal tract, the urinarytract, the upper and lower\nrespiratory system, the diaphragm, the pleura and the pericardium, as well as abdominal scars loci have been\nreported in the literature. There are several theories about the pathogenesis and the pathophysiology of\nendometriosis. Depending on the place of endometrial tissue implantation, endometriosis can be expressed with a\nwide variety of symptoms. The diagnosis of this entity is neither easy nor routine. Many diagnostic methods clinical\nand laboratory have been used, but none of them is the golden standard. The multipotent localization of\nendometriosis in combination with the wide range of its clinical expression should raise the clinical suspicion in\nevery woman with periodic symptoms of extrapelvic organs. Finally, the therapeutic approach of this clinical entity\nis also correlated with the bulk of endometriosis and the locum that it is found. It varies from simple observation, to\nsurgical treatment and treatment with medication as well as a combination of those.\nVirtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/\nvs/1968087883113362.\nKeywords: Endometriosis, Lung, Ovary, Molecular pathways, Treatment\nIntroduction\nEndometriosis is defined as the presence of normal\nendometrial mucosa abnormally implanted in locations\nother than the uterine cavity. Depending on the area\nidentified, endometriosis is characterized as endopelvic\nor extrapelvic [1-8]. The endopelvic ectopic implants are\nlocated in the minor pelvis, the ovaries, the fallopian\ntubes and the uterosacral ligaments posterior of the\nuterus, whereas, the more unusual extrapelvic implant-\nation sites are the abdominal wall, scars of the perineum,\nthe urinary and gastrointestinal tract, the thorax and the\nnasal mucosa. Endometriosis can affect any woman from\npromenarche until postmenopause, regardless the race\nor ethnicity and her maternal status [9].\nEndometriosis is the most common cause of chronic\npelvic pain in females. Its prevalence has been estimated\nto 1-2% of reproductive age females and its more common\n(15-25%) among women with infertility problems [10].\nThe prevalence is 40-60% among women with dysmenor-\nrhea and it is extremely rare after menopause, because of\nthe estrogen dependence of the ectopic tissue [10]. The\nrelapse of endometriosis during menopause has been\ncorrelated with hormonal replacement therapy [11].\nEndometriosis is not related with endometrial cancer.\nCurrent research has demonstrated a relationship between\nendometriosis and certain types of neoplasms mainly\novarian cancer, non-Hodgkin lymphoma and brain\ncancer [12,13]. Endometriosis often coexists with fibroid\nor adenomyoma, and autoimmune disorders. A survey\n* Correspondence: pzarog@hotmail.com\n4Pulmonary Department, “G. Papanikolaou ” General Hospital, Aristotle\nUniversity of Thessaloniki, Exohi 1100, 57010 Thessaloniki, Greece\nFull list of author information is available at the end of the article\n© 2013 Machairiotis et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the\nCreative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public\nDomain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this\narticle, unless otherwise stated.\nMachairiotis et al. Diagnostic Pathology 2013, 8:194\nhttp://www.diagnosticpathology.org/content/8/1/194\n\nconducted in 1988 in the U.S. found significantly higher\nprevalence of cases of hypothyroidism, fibromyalgia, chro-\nnic fatigue syndrome, autoimmune diseases, allergy and\nasthma in women with endometriosis compared to the\ngeneral population [14].\nMechanism of the pathogenesis of endometriosis\nEndometriosis is one of the most enigmatic and mysteri-\nous gynecological diseases [15]. The etiology and patho-\ngenesis, knowledge of which is the basis of dealing with\nit, still remains very unclear. Since 1860, when Von\nRokitanski [16] made the first detailed description of this\ncondition, many theories have been developed for the\netiology and pathogenesis of endometriosis, but none\nfully meets the pathological entity. The first thoughts\nabout the etiology-pathogenesis of endometriosis were\nmade in 1885 by Von Recklinghausen, who considered\nthat embryonic mesonephric elements are responsible\nfor the development of endometriosis [17]. The view of\nVon Recklinghausen was adapted in 1942 by Grunwald\nwho argued that during the fetal cells from the growing\nresources Muller can acquire the ability to convert them\ninto endometrial cells [18].\nCurrently three theories seem to represent the current\nscientific thinking. These are the theory of metaplasia\n(metaplasia theory), the theory of dispersion and ‘trans-\nplantation’ of endometrium and the theory of induction.\nIt is of great importance to refer that these three theor-\nies are the “core” of the current scientific thinking and\nthere are many elements added to this core creating a\nvariety of theories. On the other hand, nowadays, as a\nresult of extensive literature research there is scientific\nevidence questioning the existence of endometriosis as a\nsingle entity and the accuracy of the theories above.\nThe first theory is the theory of metaplasia of the peri-\ntoneal serosa cuff. This theory was proposed by Meyer\nin 1903 [17]. According to this theory, the development\nof the disease is a result of a continuous process of tissue\ndifferentiation of mesothelial cells of the peritoneum\nunder the effect of inflammatory or hormonal factors,\nresulting in the formation of cell clusters which grad-\nually sink to the underlying organs while they are\nreshaping in endometrial glands and stroma. This theory\nthat found great popularity in the early decades of the\ntwentieth century could explain the development of\nendometriosis in women with agenesis resources Muller.\nBut there are several problems and questions, which\ncannot be answered by this theory. However, the theory\nof metaplasia, can explain the development of endomet-\nriosis in distant organs.\nThe second theory of the aetiology and pathogenesis\nof endometriosis is that of endometrium dispersion and\n‘transplantation’. The dispersion of endometrial cells\nthrough the lymphatic vessels was proposed by Halban\non 1924 in order to interpret the extrapelvic localiza-\ntions of endometriosis [18]. The hematogenous spread\nwas supported on the same basis by Sampson on 1925\n[19]. Histologic confirmation of this theory was made by\nJavert on 1952, who proved the presence of endometrial\ntissue in pelvic veins [20]. The mostly understood and\naccepted theory is the theory of dispersion proposed in\nthe 1920s by Sampson, who supported that during the\nmenstruation, retrograde dispersion of living endomet-\nrial cells can occur in the peritoneal cavity and ovaries.\nThe third theory is that of induction, which can be con-\nsidered as a combination of the two previous theories\n[21]. According to this theory, unknown substances, are\nreleased from the endometrium and cause transformation\nof undifferentiated mesenchymal cells to endometrial\ntissue. This theory is supported experimentally by Merril,\nwhich caused peritoneal endometriosis in rodents, im-\nplanting in the peritoneal cavity filters of live endometrial\ntissue [22].\nMost of the modern theories of endometriosis patho-\ngenesis consist of the following additional areas:\nEstrogens: Endometriosis is a condition that is\nestrogen-dependent and therefore is considered to\noccur mainly during the reproductive age [ 10]. In\nexperimental models, estrogens are necessary in order\nto induce or preserve endometriosis. The treatment\noften aims at the reduction of the estrogen levels in\norder to control the disease.\nGenetics: Hereditary factors appear to play a role. It is\nknown that the daughters or sisters of patients with\nendometriosis are at higher risk of developing\nendometriosis themselves. For example, the low levels\nof progesterone may have a genetic etiology, and can\ncontribute to a hormonal imbalance. There is an\napproximately 10-fold increase in the disease incidence\nin women with affected first-degree relative [ 23]. A\n2005 study published in the American Journal of\nHuman Genetics has shown an association between\nendometriosis and chromosome 10q26 [ 24], while a\n2010 study in Nature Genetics identified association\nwith the region 7p15.2 [ 25]. One study found that\nwomen-siblings of patients with endometriosis, the\nrelative risk for endometriosis is 5.7:1 versus the\ngeneral population [ 26].\nTransplantation: It is widely accepted that in specific\npatients endometriosis can spread directly. Thus,\nectopic endometrial tissue is found in abdominal\nsurgical scars after surgery for endometriosis [ 9].\nImmune System: The research focuses on the possibility\nthat the immune system may not be able to cope with\nretrograde menstruation. In this context, there is\ninterest in studying the relationship between\nendometriosis and autoimmune disease, allergic\nMachairiotis et al. Diagnostic Pathology 2013, 8:194 Page 2 of 12\nhttp://www.diagnosticpathology.org/content/8/1/194\n\nreactions, and action of toxins [ 27,28]. It is still\nunclear what, if any, the causal relationship\namong toxins, autoimmune disease, and\nendometriosis is.\nContext: There is a growing suspicion that\nenvironmental factors may cause endometriosis,\nspecifically some plastics and cooking with certain\ntypes of plastic containers with microwaves [ 29] and\nthe effect of dioxin [ 30,31]. Other sources indicate\nthat pesticides and hormones in our food cause a\nhormonal imbalance.\nCongenital defect: In rare cases where the atretic\nhymen is not terminated before the first menstruation\nand remains trapped inside the patient ’s uterus until\nthe problem is resolved with surgical resection. Many\nhealth care professionals do not address this flaw, and\noften overlooked until multiple menstrual periods\nto spend.\nHowever, the most widely accepted theory for the\npathogenesis of endometriosis is the theory of ectopic\nendometrial implantation via retrograde menses [32].\nSimilarly, endometriosis in distant parts of the body can\nbe explained by the migration of cells of the endometrium\nthrough lymphatic and blood vessels [33]. Thus, endo-\nmetriosis is a unique example of benign proliferation and\nmetastasis [34].\nAt cellular level, endometriosis is characterized by\ndevelopment of monoclonal tissue and may have\ncharacteristics of malignant behavior, including local\nand metastatic filtration. As a result of this endomet-\nriosis can be used as a model to study the molecular\nand genetic conditions needed for dispersion or non-\nmalignant cells.\nGenerally, the correlation between endometriosis and\ncancer is unclear. Although endometriosis is a non-\nneoplastic disease, and does not cause catabolic syndrome\nand cahexia, other procedures, which characterize the\ncarcinogenesis and metastasis are also present in endo-\nmetriosis. These include cell motility, cell adhesion and\ninfiltration, immunological factors, maintaining the ori-\nginal structure and architecture of the tissues in ectopi-\ncally points, angiogenesis and metaplasia [35].\nFurthermore, there is evidence that endometriosis\nhas genetic alterations similar to some cancer types\n[35,36], while a direct correlation between ovarian\ncancer and endometriosis has been previously de-\nscribed in some reports and clinical trials [13,37-39].\nLike any other tissue, endometrial tissue can also\nundergo malignant transformation. On the contrary,\nlarge retrospective epidemiological studies suggest\nthat women with endometriosis have an increased risk\nof ovarian and some other cancers compared to the\ngeneral population [40-42].\nThe role of the extracellular matrix enzymes in endometriosis\nA series of studies has shown that several enzymes of\nthe extracellular matrix act to endometriosis or in nor-\nmal endometrium of women with endometriosis, leading\nto self-destruction of the extracellular matrix. Thereby,\nfacilitating the penetration of epithelial cells in deeper\nlayers of the endometrium, which are required either for\nlocal development of endometriosis foci or disease\nspread. Of the various enzymes of the extracellular\nmatrix which act in this manner have been studied\nmainly the system of metalloproteinases and the plas-\nminogen system.\nThe system of metalloproteases or matrix metallopro-\nteinase (MMP-matrix metoloproteases or metallopro-\nteinases) comprises an enzyme component, the MMPs,\nand by an inhibitory element of enzymes, the tissue in-\nhibitor of metalloproteases the TIMPs (tissue inhibitor\nof metaloproteases) [43]. It is well documented that the\nsystem of MMPs plays a key role in the normal develop-\nment and growth of the endometrium and many other\nphysiological processes in other tissues. Because of the\nnecessity for balance between MMPs and TIMPs, it is\nnot surprising that a differential expression of MMPs\nand TIMPs is associated with the pathophysiology of\nendomiolysis and the imbalance between the secretion\nof MMP-9 and its natural inhibitor TIMP-1 in the\nculture milleu of endometriosis tissue probably reflects\nthe increased ability of this tissue in vivo to cleave the\nextracellular matrix, thereby facilitating the ectopic im-\nplantation of endometrial growth.\nThe potential role of MMP-9 and TIMP-1 in the\npathogenesis of endometriosis has also been studied in\nthe peritoneal fluid of women with endometriosis by\nStamatowicz et al. [44]. The findings of this study also\nagree with the hypothesis that the imbalance between\nMMP-9 and TIMP-1 may play an important role in the\npathogenesis of the disease.\nThe Gaetje et al. [45] studied the expression of\nMMP-5-type membranes with microarrays and real\ntime PCR. This study showed that the endometrium,\nand this part of the system of matrix metalloproteases\ncontribute in an increased tissue remodeling (tissue\nremodeling) and allow cell migration in patients with\nendometriosis.\nThe Gillabert-Estelles et al. [46] studied the expression\nof angiogenic factors in endometriosis and their relation-\nship with the system of matrix metalloproteinases. In\nthis study, there was a significant increase in the peri-\ntoneal fluid of women with endometriosis, the levels of\nvascular endothelial growth factor (Vascular Endothelial\nGrowth Factor-VEGF), the urokinase-type plasminogen\nactivator (urokinase-type Plasminogen Activator-uPA)\nand the levels of MMP-3 in comparison with women-\nwitnesses without endometriosis.\nMachairiotis et al. Diagnostic Pathology 2013, 8:194 Page 3 of 12\nhttp://www.diagnosticpathology.org/content/8/1/194\n\nThe MMP-3 and uPA were also studied by Ramon et al.\n[47] using quantitative realtime RT-PCR. In this study,\nthere was an increase in the levels of uPA and MMP-3 in\nthe endometrium of women with endometriosis, which\ncan facilitate the adhesion of endometriosis tissue in the\nperitoneum and the surface of the ovary, and the penetra-\ntion of the extracellular matrix, with the last one resulting\nin the formation of early endometriosis foci.\nAnother study, by Gillabert-Estelles et al. [48], reached\nsimilar conclusions. In this work, the scientists analyzed\nthe expression of different members of the plasminogen\nactivator and MMPs systems of endometriosis and found\nthat the ovarian endometriosis tissues had higher levels of\ninhibitor of plasminogen activator 1 (Plasminogen Activa-\ntor Inhibitor-PAI-1) and TIMP-1, compared to normal\nendometrium.\nThe overall conclusion is that the increase of uPA and\nMMP-3 in the endometrium of women with endometri-\nosis leads in an increase in the invasive capacity of endo-\nmetriosis cells. Since endometriosis creates a corner an\nincrease in PAI-1 and TIMP-1 is detected, resulting in\nthe cessation of further proteolytic activity.\nThe growth stop and the decrease in the proteolytic\nactivity could also explain the frequent clinical finding of\nisolated endometriosis cysts without infiltration of the\nsurrounding ovarian tissue.\nIn another study, Chung et al. [49] analyzed the ex-\npression of MMP-9 and TIMP-3 in normal and ectopic\nendometrium of women with endometriosis. Their find-\nings show that both ectopic and normal endometrium of\npatients with endometriosis, may be more invasive and\nmore capable of being implanted in the peritoneum\nbecause of the increased expression of MMP and de-\ncreased expression TIMP-3 in comparison with women\nwithout endometriosis.\nThe expression of another member of the MMPs\nfamily, the MMP-2, analyzed by Kim et al. [50] together\nwith the expression of CD44s, of VEGF and Ki-67 in\nperitoneal, and ovarian endometriosis. In red and white\nendometriosis, there was a higher expression of MMP-2 in\nlayer than in black homes. Also, the expression of MMP-2\nwas significantly elevated in advanced endometriosis\n(stages III and IV according to the revised classification of\nthe American Fertility Society), indicating that MMP-2\nmay be responsible for the development of endometriosis.\nSimilar findings in terms of the MMP-2 and VEGF were\nalso present in an experimental model in mice [51].\nLike the other members of the family of MMPs, so the\nMMP-1 appears to play a role in the mechanisms of\nlocal perfusion. The Hudelist et al. [52] noticed that\ninterleukin-1 and MMP-1 are increased in ectopic endo-\nmetrium of patients with endometriosis, suggesting their\ninvolvement in the pathogenetic mechanisms that lead\nto local invasion and tissue destruction.\nSummarizing the findings of the literature, it is clear\nthat the family of matrix metalloproteinases (MMPs)\nand their natural antagonists, inhibitors of metallo-\nproteases (TIMPs), and the plasminogen system play an\nimportant role in the pathogenesis of endometriosis.\nHowever, it is still necessary, to conduct a substantial\nresearch effort to identify molecules which are more\nimportant in the mechanism of creation and develop-\nment of endometriosis, and discovery of molecules\nwhich would be more suitable as markers of disease\nand as targets in which therapeutic models (Table 1)\n(Figures 1, 2, 3, 4, 5, 6, 7).\nDiagnostics of endometriosis\nSome laboratory and imaging methods may help to diag-\nnose the disease, but none of them alone is enough to\ndiagnose endometriosis. Most often the diagnosis is\nmade based on a combination of typical symptoms and\nclinical findings. Studies have shown that the diagnosis\nof endometriosis is earlier in women who are tested for\nsterility than in those with pelvic pain, in which the\ndisease is diagnosed in more advanced stages, mainly\ndue to the late visit to a gynecologist [9,53].\nThe main diagnostic methods for diagnosis of endo-\nmetriosis are:\nUltrasonography: From the available imaging\ntechniques, ultrasound has been proven useful in\nthe diagnosis of endometriosis.\nMagnetic Resonance Tomography (MRI): In\ncontroversial cases can confirm the diagnosis of\nendometriosis and to rule out other diseases.\nDiagnostic laparoscopy with biopsy tissue remains\nthe most reliable diagnostic method.\nThe only way to diagnose endometriosis is by laparos-\ncopy or other types of surgery including biopsy of the\nlesion. The diagnosis is based on the characteristic appear-\nance of the disease, and should be confirmed by biopsy.\nThe surgery also allows for diagnosis of the surgical treat-\nment of endometriosis at the same time [53,54].\nBiochemical markers\nOne area of diagnostic research is the search for markers\nof endometriosis. These markers are substances pro-\nduced by or for the treatment of endometriosis and\ndoctors can measure in biopsies, blood or urine. The de-\ntection of such an index can lead to early diagnosis of\nendometriosis that can be achieved by the rather non-\nspecific symptoms, and can replace the invasive surgical\nprocedures in the diagnosis of disease [55]. A biomarker\ncould also be used to identify the first signs of thera-\npeutic efficacy or recurrence of disease, because the\nsymptomatic relief or deterioration is usually difficult to\nMachairiotis et al. Diagnostic Pathology 2013, 8:194 Page 4 of 12\nhttp://www.diagnosticpathology.org/content/8/1/194\n\nFigure 1 Clusters of endometrial glands and stroma in fallopian\ntube wall with inflammation (H&E X100).\nFigure 2 Nests of endometriosis into the rectus abdominis\nmuscle (H&E X100).\nTable 1 Molecular pathways of endometriosis\nPast theories\nVon Recklinghausen (1885) Embryonic mesonephric elements\nGrunwald (1942) Fetal cells of Muller resources can be converted into endometrial cells\nMetaplasia theory (Meyers 1903) Metaplasia of the peritoneal serosa cuff differentiation of mesothelial cells of\nthe peritoneum\nTheory of dispersion and transplantation (Halban, Sampson) Dispersion of endometrial cells through lymphatic vessels and hematogenous spread\nTheory of induction (Merril) Combination of the previous theories\nModern theories combine\nEstrogens Estrogen dependent\nGenetics Hereditary (10q26, 7p15.2)\nTransplantation Direct spread\nImmune system Incapability of the immune system\nContext Environmental factors\nCongenital defect Atretic hymen\nEctopic endometrial implantation via retrograde menses\nCellular level Development of monoclonal tissue with characteristics of malignant behavior\nMolecular level Enzymes of the extracellular matrix act to endometriosis or in normal endometrium\nof women with endometriosis\nMMP-9/TIMP-1 Stamatowicz et al.\nMMP-9/TIMP-3 Chung et al.\nMMP-5 type membranes increase Gaetje et al.\nMMP-3/uPA Ramon et al.\nVEGF/MMP-3/uPA Gillabert –Estelles et al.\nVEGF/MMP-2/CD44/Ki67 Kim et al.\nPAI/TIMP-1 Gillabert –Estelles et al.\nIL-1/MMP-1 Hudelist et al.\nMachairiotis et al. Diagnostic Pathology 2013, 8:194 Page 5 of 12\nhttp://www.diagnosticpathology.org/content/8/1/194\n\nquantify [55]. However, since the benefits of the treat-\nment of women with asymptomatic endometriosis are\nunclear, it is likely that any biomarker could be used\nonly for the screening of women with symptoms sug-\ngestive of endometriosis [55]. Therefore, a predictive\nbiomarker should distinguish between women with\nendometriosis than women with similar symptoms (for\nexample, dysmenorrhea, pelvic pain or infertility [55].\nA systematic study in 2010 for all proposed bio-\nmarkers of endometriosis in serum, plasma and urine\nconcluded that none of them have been clearly shown to\nbe of clinical use, although some seem to be promising\n[55]. Another study in 2011 identified several biomarkers\nsupposedly after biopsy, including small sensory nerve\nfibers or reduced expression of b3 integrin subunit [56].\nA biomarker has been used in clinical practice in the\nlast 20 years is the CA-125 [13]. However, the perform-\nance in the diagnosis of endometriosis is low, but it\nseems to have an effect on the detection of more severe\ndisease [55]. The CA-125 levels seem to fall during the\ntreatment of endometriosis, but do not show any correl-\nation with the therapeutic response [55].\nFurther research is also conducted for other potential\ngenetic markers related to endometriosis that can replace\nsurgical procedures for basic diagnosis [56].\nFinally, a group of several biomarkers has been sug-\ngested as a future diagnostic tool for endometriosis,\nincluding both the concentrations of substances and\ngenetic predisposition [55].\nAbdominal wall endometriosis\nAbdominal wall is the most frequent location of\nextrapelvic endometriosis [57]. Endometriosis of the\nabdominal wall is usually associated with a surgical\nprocedure in the uterus especially in women who have\nbeen delivered a cesarean section scar [58-63]. The most\nFigure 3 Focal endometriosis in a lymph node (H&E X100).\nFigure 4 Endometrial glands and stroma with hemorrhange\nand hemosiderin-laden macrophages into the muscularis\npropria of large bowel (H&E X100).\nFigure 5 Nests of endometriosis into the muscularis propria of\nsmall bowel (H&E X40).\nFigure 6 Endometrial glands and stroma into the dermis, close\nto cesarean section scar (H&E X100).\nMachairiotis et al. Diagnostic Pathology 2013, 8:194 Page 6 of 12\nhttp://www.diagnosticpathology.org/content/8/1/194\n\ncommon clinical symptom in women with abdominal\nwall endometriosis is a constant focal abdominal pain\nwhich is mostly not associated with the menstrual cycle\n[59-62]. This pain is frequently atypical so it can be\nmisdiagnosed. Patients can also feel a papable mass in\nthe area of the surgical section.\nDiagnostic methods for showing an abdominal endome-\ntrioma are: ultrasound sonography, computer tomography\nand magnetic resonance tomography (MRI).\nUltrasound sonography is not specific diagnostic method\nfor an abdominal endometrioma, thus it shows a\nm a s si nt h ea b d o m i n a lw a l l .T h i sm a s si si m a g e da sa\nsolid, hypoechoic lesion containing internal vascularity\nand it may also contain cystic areas. This abdominal\nmass must be submitted to differential diagnosis. This\ndifferential diagnosis includes neoplasms (like sarcoma\nor lymphoma), suture granuloma, ventral hernia,\nabscess or haematoma [64,65]. The latter three can\nbe excluded from the final diagnosis of endometrioma\nby ultrasound sonography.\nCT and MRI also show a solid mass in the abdominal\nwall, so they cannot be specific diagnostic methods of an\nendometrioma, but they can depict the extent of the\ndisease preoperatively [66,67] (Figures 8, 9, 10).\nThough, sonographicaly guided FNA seems to be the\nmost accurate diagnostic method for women with abdo-\nminal wall masses. Νevertheless, additional histological\nbiopsy may be performed.\nThe best treatment of abdominal wall endometriosis is\nthe wide surgical excision [9,58].\nEndometriosis of the thorax\nEndometriosis of the thorax is a clinical entity that\nincludes the presence of ectopic endometrial tissue in\nthe pleura, the pericardium and rarely the diaphragm.\nThis is often expressed as catamenial pneumothorax.\nCatamenial pneumothorax is the most common clinical\nexpression of thoracic endometriosis syndrome, which\nincludes four other entities. These are in brief, catame-\nnial hemothorax, catamenial hemoptysis, endometriotic\nlung nodules, and catamenial chest pain. The catamenial\ncharacter of all these symptoms mentioned above is a\nresult of the menstrual cycle [68].\nMore specifically, for the development of catamenial\npneumothorax the presence of endometrial tissue in the\nthoracic cavity is necessary. There are many theories try-\ning to explain this phenomenon. The theory of Suginamy\net al. suggests that endometrial tissue may circulate along\nwith the peritoneal fluid in the abdominal cavity following\nac i r c l e“route” down the left peritoneal gutter over the\npelvic floor and up the right gutter to the peritoneal\nsurface of the diaphragm. This “route” explains the\nincreased frequency of catamenial pneumothorax of the\nright side [69].\nFigure 7 Nests of endometriosis in a fibrous backround, close\nto cesarean section scar (H&E X100).\nFigure 8 MR images demonstrate foci of endometriomas at the\nsites of the section [T-2 w.i].\nFigure 9 Endometrioma in the abdominal wall at point of the\ncesarian section [T-1w.i. and fat saturation technique].\nMachairiotis et al. Diagnostic Pathology 2013, 8:194 Page 7 of 12\nhttp://www.diagnosticpathology.org/content/8/1/194\n\nThe next question that rises after the description of\nthis scenario is how these endometrial particles reach\nthe pleura and the lung. Despite the fact that there are\nsmall peritoneal stomata, which allow the trespassing of\nparticles below 30 Îm, to enter the diaphragmatic lacu-\nnae, a defect of the anatomical continuity of the dia-\nphragm must also exist in order to allow air to pass and\ncause pneumothorax [70].\nAnother theory of the pathogenesis of catamenial\npneumothorax was announced by Kirschner et al., who\nnamed it “porous diaphragm syndrome ”. According to\nthis theory preexisting diaphragmatic lesions allow fluid\nand gas to traverse the diaphragm and that the common\ndevelopment of pneumothorax in the right side is a\nresult of the presence of the liver and the valve effect\nthat it can cause to the intraperitoneal pressure [71].\nThe other four clinical entities that form the thoracic\nendometriosis syndrome such as catamenial hemoptysis,\ncatamenial hemothorax, lung nodules and catamenial\nchest pain can be a result of the lung lesions caused by\nthe metastatic spread of endometrial tissue. In fact endo-\nmetrial cells have been shown to embolize peripheral\nblood vessels of the lung as well as to invade the respi-\nratory epithelium [70]. Another cause of catamenial\nhemoptysis can be the mensessynchronous increase of\nprostagalandine F2, which may cause rupture of bullae\nand blebs that may exist in normal lungs [70]. Addition-\nally, to the cases of endometriosis of the lower respira-\ntory system, there are two case reports in the literature\ntha refer to upper respiratory system endometriosis and\nmore specifically to nasal endometriosis. Nasal endo-\nmetriosis causes cyclic epistaxis and nasal pain, which is\nsynchronous to the menstrual cycle [72] (Figure 11).\nEndometriosis of the gastrointestinal tract\nExtrapelvic endometriosis can also be located in the liver\nand the gallbladder, but these entities are extremely rare.\nThere are approximately fourteen cases in the interna-\ntional literature about liver endometriosis and in most of\nthem the patients were suffering from pain and a feeling\nof weight in the right upper quadrant of the abdo-\nmen. There are also cases of liver endometriosis that\nwas present with the clinical expression of obstructive\njaundice [73-77].\nEndometriosis of the gallbladder is extremely rare.\nThere are two case reports in the literature referring to\nthe diagnosis of gallbladder endometriosis [78].\nIn some women endometriosis occurs in the gastro-\nintestinal tract. This is called intestinal endometriosis.\nThe common endometriosis bowel symptoms are the\nrectal bleeding and pain, the painful bowel move-\nments, the loss of appetite, the cramping stomach\npains, the nausea and vomiting, the constipation and/\nor diarrhea, the abdominal bloating and gas in the ab-\ndomen. All these symptoms are getting worse during\nmenstruation [79-82].\nThe most common location of extrapelvic intestinal\nendometriosis is the last part of the ileum (the small\nintestine), the cecum (the first part of the large bowel),\nand the appendix [83].\nUrinary tract endometriosis\nEndometriosis of kidney is a rare condition. The\ncommon symptoms of renal endometriosis are local pain\nand rarely cyclical hematuria. It usually comes suddenly\nas a clinical manifestation. Sometimes the lesion may be\ntotally asymptomatic and may diagnosed after nephrec-\ntomy for presumed renal cell carcinoma [84,85].\nIn ureteral endometriosis, ureteral involvement is\noften limited to one ureter, most commonly the left.\nTwo major pathological types exist: extrinsic and intrin-\nsic ureteral endometriosis. In the most common extrin-\nsic type endometrial glandular and stromal tissue and\nthe adventitia of the ureter or surrounding connective\ntissues are involved. In the intrinsic type muscularis\npropria, lamina propria, or ureteral lumen are involved\n[86,87]. Ureteral endometriosis can lead to urinary\ntract obstruction with subsequent hydroureter and\nhydronephrosis and even loss of renal function which\nis rare [88].\nFigure 10 Endometrioma after enhanced T-1 w.i. and fat\nsaturation technique.\nMachairiotis et al. Diagnostic Pathology 2013, 8:194 Page 8 of 12\nhttp://www.diagnosticpathology.org/content/8/1/194\n\nRare locations of endometriosis\nAmong the other rare locations of endometriosis it is\nimportant to refer the endometriosis of large muscles\nsuch as the adductor compartment [89], the endometri-\nosis of the rectus abdominis muscle [90], endometriosis\nof the gluteal muscle, which can be cause catamenial\nsciatica [91]. There is one case report in the literature\nabout nerve endometriosis. More specifically, it was\nendometriosis of the L5 nerve that caused gluteal atro-\nphy and sciatica [92].\nTreatment\nThe therapeutic options in the treatment of endome-\ntriosis depend on the extent of the disease, the patient ’s\nneeds and the desire to maintain the reproductive\ncapacity. These options include:\n1) simple observation,\n2) surgical treatment,\n3) medical treatment and\n4) combined therapy.\nSimple observation\nIn the past the simple observation without any interven-\ntion was considered appropriate for the initial stages of\nthe disease when no symptoms or are simply limited.\nToday therapeutic intervention after diagnosis of endo-\nmetriosis is necessary as the lesions of the disease\nincreases with time [93].\nConservative surgical treatment\nApply to patients who wish to preserve their reproduct-\nive capacity and may include removal or destruction\n(evaporation laser, electrocautery, thermal coagulation)\nsurface lesions or endometriomas (cysts), which com-\nbined with cleaning of adhesions and restoring normal\nanatomy. The surgical treatment of the disease is either\nlaparoscopy or laparotomy (open surgery). Regardless of\nthe surgical technique (laparoscopy or laparotomy), re-\nmoval of all endometrial lesions with careful cleaning of\nadhesions is necessary to address the pelvic pain and\ninfertility in women who wish to preserve their repro-\nductive ability [10].\nDrug treatment\nTheoretically, drug treatment would be ideal in the\ntreatment of endometriosis. In practice, however, drug\ntherapy alone is accompanied with a temporary impro-\nvement of pain, and tampering of the symptoms but in a\ntime period they usually return. Also, drug therapy can\ncertainly reduce the size of endometriomas and facilitate\ntheir removal surgery. Contraceptive pills are one of the\nFigure 11 Hematoxylin and eosin (H&E). A : The alveolar spaces were filled with many red blood cells and phagocytic cells with hemosiderin\n(heavy arrowhead). The alveolar walls were infiltrated by plasma cells (triangulate arrowhead) and lymphocytes (light arrowhead); 200×.\nImmunohistochemical staining, B: Gland epithelium in an alveolus, CK7+ (heavy arrowhead). Infiltrating plasma cells and lymphocytes in the\nalveolar wall, CK7- (light arrowhead), H&E 200×, C: Phagocytic cells in the alveolar space, CD68+ (heavy arrowhead). Plasma cells and lymphocytes\nin the alveolar walls, CD68- (light arrowhead), H&E 200×. D: Atypical tubular-gland structures of decidual lesions were detected in the alveolar\nspace (light arrowhead). Structure of alveolar wall (heavy arrowhead); 100×.\nMachairiotis et al. Diagnostic Pathology 2013, 8:194 Page 9 of 12\nhttp://www.diagnosticpathology.org/content/8/1/194\n\nmain drug treatments, causing reduction of the quantity\nof blood and in that way they result in reducing pain\nduring menstrual period. Additionally, Gonadotropin-\nreleasing hormone (GnRH) agonists block the produc-\ntion of ovarian-stimulating hormones, lowering estrogen\nlevels and preventing menstruation. This causes endo-\nmetrial tissue to shrink. GnRH agonists can force endo-\nmetriosis into remission during the time of treatment\nand sometimes for months or years afterwards The\neffectiveness of drug therapy on the reproductive\ncapacity is questionable. That is the reason why drug\ntherapy is not recommended as the sole treatment of\nwomen with endometriosis, except for rare cases where\nsurgery is not possible or presents a significant risk for\nthe life of the patient [94-96].\nCombination therapy\nThe most effective way of treating endometriosis is the\ncombination of surgical removal of all visible endomet-\nrial lesions and medication [97,98].\nConclusion\nEndometrium is one of the most extraordinary tissues of\nthe human body. The ability of endometrium to be im-\nplanted in different tissues and simultaneously to main-\ntain its functionality is very impressive. It also explains\nthe variety of symptoms that are components of endo-\nmetriosis syndrome. Pain is the main but not the only\nand not the pathognomonic characteristic of endometri-\nosis [53]. Only the catamenial character of the symptoms\ncan be considered as more indicative of this entity. In\nconclusion, endometriosis is a common clinical entity\neven in its extrapelvic form. Every clinician should have\na high suspicion if it in cases of women with periodical\nsymptoms [99,100]. The importance of the high clinical\nsuspicion is a result of the effectiveness of the treatment.\nCompeting interests\nThe authors declare that they have no competing interests.\nAuthors’ contributions\nNM, PZ, AS wrote the manuscript, ES, NK, TS, AB and LS provided the\npathological images and wrote the legends. AG provided useful insights\nas an expert pathologist, KZ and CM provided useful insights regarding\nextrapelvic lesions, PK and NT gathered the necessary references, NC\nprovided and explained the radiologic findings. All authors read and\napproved the final manuscript.\nAuthor details\n1Obstetric - Gynecology Department, ”Thriassio” General Hospital of Athens,\nGeorge Genimata, 19600 Athens, Greece. 2Surgery Department, “Thriassio”\nGeneral Hospital of Athens, George Genimata, 19600 Athens, Greece.\n3Internal Medicine Department, General Hospital of Syros, Nikiforou\nMandilara, 84100 Island of Syros, Greece. 4Pulmonary Department, “G.\nPapanikolaou” General Hospital, Aristotle University of Thessaloniki, Exohi\n1100, 57010 Thessaloniki, Greece. 51st Internal Medicine Department,\n“Thriassio” General Hospital of Athens, George Genimata, 19600 Athens,\nGreece. 6Surgery Department (NHS), University General Hospital of\nAlexandroupolis, Nea Makri, 68100 Alexandroupolis, Greece. 7Radiology\nDepartment, University General Hospital of Alexandroupolis, Nea Makri,\n68100 Alexandroupolis, Greece. 8Internal Medicine Department,\n“Theiageneio” Anticancer Hospital, Alexander Simeonidi 2, 54007 Thessaloniki,\nGreece. 9Pathology Department, Hospital of Amberg, Mariahilfbergweg 5-7,\n92224 Amberg, Germany. 10Pathology Department, “G. 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Acien P, Velasco I: Endometriosis: a disease that remains enigmatic.\nISRN Obstet Gynecol 2013, 2013:242149.\n100. Bailly E, Margulies AL, Letohic A, Fraleu-Louer B, Renouvel F, Panel P:\n[Evolution of symptoms and quality of life of patients after surgery of\ndigestive endometriosis]. Gynecol Obstet Fertil 2013, 41(11):627-634.\ndoi:10.1016/j.gyobfe.2013.09.010. Epub 2013 Oct 30.\ndoi:10.1186/1746-1596-8-194\nCite this article as: Machairiotis et al. : Extrapelvic endometriosis: a rare\nentity or an under diagnosed condition? Diagnostic Pathology 2013 8:194.\nSubmit your next manuscript to BioMed Central\nand take full advantage of: \n• Convenient online submission\n• Thorough peer review\n• No space constraints or color figure charges\n• Immediate publication on acceptance\n• Inclusion in PubMed, CAS, Scopus and Google Scholar\n• Research which is freely available for redistribution\nSubmit your manuscript at \nwww.biomedcentral.com/submit\nMachairiotis et al. Diagnostic Pathology 2013, 8:194 Page 12 of 12\nhttp://www.diagnosticpathology.org/content/8/1/194","source_license":"CC0","license_restricted":false}