{"paper_id":"970b93dd-01c6-45ce-88e0-415938ae031a","body_text":"Research Article\nLungs and Breathing\nLung Breath J, 2017          doi: 10.15761/LBJ.1000119\n Volume 2(1): 1-5\nISSN: 2515-1010 \nPulmonary endometriosis: Clinico-pathological approach \nto diagnostics and treatment\nDvorakovskaya IV1, Pechenikova VA2, Ariel BM3,6*, Platonova IS1, Orzheshkovskiy OV4,5, Pichurov AA5, 6 and Yablonskiy PK1,4,6\n1Institute for Pulmonologic Research, Academician I.P.Pavlov’s St Petersburg State First Medical University, Healthcare Ministry of Russian Federation, Russia\n2 I.I.Mechnikov’s State North-West Medical University, Healthcare Ministry of Russian Federation, Russia\n3City of St Petersburg State Bureau for Pathology, Russia \n4St Petersburg State University, Russia\n5State Multidisciplinary Hospital No.2, St Petersburg, Russia\n6St Petersburg Federal Research Institute of Phthisiology and Pulmonology, Healthcare Ministry of Russian Federation, Russia\nAbstract\nBackground: A pulmonary endometriosis is one of the relatively rare forms of the extragenital endometriosis and in accordance to its clinico-pathological symptoms \nis considered within the terms of the “thoracic endometriosis syndrome”, i.e. when functioning endometrium is found in the pleura, diaphragm, viae respiratoriae or \nthe pulmonary parenchyma itself. \nObjectives: 42 cases of this disease were observed. The patients age ranged from 16 to 61 years, thus the average being 40.5 ± 0.4 years. \nResults: In the majority of cases the endometriosis affected the diaphragm and was accompanied by a pneumothorax with the corresponding symptoms complex, \nwhile pulmonary foci occurred rarer, being asymptomatic or feigning some surgical and other pathology. The surgery and the histological study were crucial in \nverifying the diagnosis. Progesterone and estrogen receptors, and Ki-67 production were detected immuno-histochemically in the endometrioid tissue of the lung foci. \nConclusion: The use of the comprehensive histological and immuno-histochemical methods was required to make the final diagnosis of the pulmonary endometriosis \nmore reliable. It has a great practical significance being one of the most important pre-requisites for prescription of an adequate treatment.\nCorrespondence to: Boris M. Ariel Saint-Petersburg Federal Research Institute \nof Phthisiopulmonology, Healthcare Ministry of Russian Federation; Ligovsky \nprospekt 2/4 193036 Saint-Petersburg Russia, Tel: (812) 534-3791; E-mail: \narielboris@rambler.ru  \nKey words: thoracic endometriosis syndrome, extragenital endometriosis, \npulmonary endometriosis, diaphragm lesion, pneumothorax, histological \nverification of diagnosis\nReceived: November 28, 2017; Accepted: December 18, 2017; Published: \nDecember 22, 2017\nIntroduction\nEndometriosis is a growth of the tissue similar to the endometrium \noutside the uterine cavity which is accompanied by a chronic \ninflammatory reaction, leading in most cases to the development of \na pain syndrome and/or infertility. Currently, it is one of the most \ncommon gynecological diseases. This pathology occurs in 2-10% \nof women of reproductive age and almost in 50% of women with \ninfertility [1,2].\nOne of the relatively rare forms of the endometriosis is characterized \nby the development of the endometrial tissue outside the reproductive \nsystem. Extragenital foci may exist independently both as separate \nformations and as components of the concomitant lesions [3,4]. The \ncases of the extragenital endometriosis make 6-8% of the total number \nof the endometriosis observed. Among the organs unrelated to the \nreproductive system, there are the intestines, the urinary tract, and the \nlungs that are most frequently affected [5].\nHart was the first to diagnose the pulmonary endometriosis (PE) \nposthumously in 1912. He observed in a woman, aged 72, numerous \nsubpleural nodes varying from the size of a pea to that of a walnut. The \nhistological examination showed adenomyosis of the uterine origin; a \ntumor in the patient’s uterus having been removed 22 years prior to \nthat [6].\nOver the last decade the number of publications on the \nendometriosis has markedly increased. The concept of the “thoracic \nendometriosis syndrome” (TES) has been developed and used in cases \nwhen the functioning endometrium is found in the pleura, the diaphragm, \nthe viae respiratoriae or the pulmonary parenchyma itself [7,8].\nChannabasavaiah and Joseph [9] have presented results of an \nanalysis of 110 clinical cases of the histologically verified intrathoracic \nendometriosis that were published between 2001 and 2007. Legras et \nal. [10] have studied retrospectively 229 cases of the pneumothorax in \nwomen described in the specialist literature written in English from \n2000 to 2011 and state that the TES being diagnosed in 54 cases (24 \nper cent). \nThe question of how a functioning endometrium gets into the chest \nremains as yet open [6, 11,12]. Sampson [13] was the first to suggest \nthat the endometrium is transferred from the uterine cavity into the \nabdominal one through the fallopian tubes by way of the so-called \n“retrograde menstruation”, that is, the discharge of some amount of \n\nDvorakovskaya IV (2017) Pulmonary endometriosis: Clinico-pathological approach to diagnostics and treatment\n Volume 2(1): 2-5\nLung Breath J, 2017          doi: 10.15761/LBJ.1000119\nblood into the pelvic cavity during menstruation. This kind of reflux \noccurs in a large number of healthy women [14]. Sampson [13] also \nhypothesized an existence of the metastatic, or embolic endometriosis, \nwhich allows one to speculate about hematogenous routes of the \nendometriosis propagation. Hobbs and Bortnick [11] confirmed this \nhypothesis experimentally introducing the endometrium suspension \ninto the ear veins of rabbits, which resulted in the development of the \nPE in 79 per cent of cases.\nThe TES manifests itself most often in the recurrent pneumothorax, \nhaemoptysis, cough or chest pain, and more rarely in the haemothorax \nassociated with the menstrual [2, 7, 15-17]. The PE is one of the rarest \nforms of the TES. The most important clinical manifestations of the \nformer are cough, haemoptysis, and a feeling of heaviness in the chest \n(a «heavy fur coat» symptom) that occur during menses, but not \nnecessarily in every menstrual cycle. \nAccording to the literature, pneumothorax associated with the TES \nis found in approximately 10-24 per cent of women with a spontaneous \npneumothorax [7, 16].\nX-rays chest examination (mainly HRCT) reveals four variants \nof the pathology: linear, or reticular opacities, small nodules, cystic \nairspaces, thickened alveolar septa. These radiological findings, \nparticularly those combined with a haemoptysis and chest pain are \noften regarded as an evidence of a tuberculous or a neoplastic nature of \nthe pulmonary lesion.\nA diaphragm lesion is usually detected by accident during a surgical \nintervention due to pneumothorax. Prior to the surgery this pathology \nis very seldom detected because of a limited extent of the lesions and \nlow resolution of radiological methods.\nAlmost without exception, the disease affects a tendinous centre \nof the right diaphragm dome and may appear in two kinds. The first \none takes the form of blue or purple endometrious implants under the \nparietal pleura up to 5 mm in size. The second are round or slit-like \ndefects in the diaphragm.\nThe lack of specific symptoms, of laboratory markers, and \ncharacteristic radiological patterns makes the preoperative diagnosis \nof PE difficult. It is often finally diagnosed only after a confirmation \nby the histological methods, among them the immuno-histochemistry, \nincluding estrogen and progesterone receptors expression [15].\nTherefore, the surgical intervention is often necessary on \ndiagnostic and therapeutic purposes. Though the operation does verify \nthe diagnosis as a rule and removes any heterotopic endometrium \nlesions, this kind of treatment remains incomplete [7, 17] without \na suppressive hormonal therapy. It aims at an ovulation blocking, a \nsuppression of the estrogen secretion and epithelial growth supression \nin the endometrious focus [18].\nA relatively small number of the TES cases described in the world \nspecialist literature and the lack of its pathognomonic clinical picture \nprompted us to summarize our own experience in the diagnostics and \ntreatment of this disease.\nMethods\nWe’ve analyzed 42 cases of the TES observed in our hospitals over \nthe period from 2004 to 2016. The patients age ranged from 16 to 61 \nyears, thus the average being 40.5±0.4 years.\n35 patients were hospitalized due to a spontaneous pneumothorax, \n3 with rounded tumorous masses, 1 with a cyst, and 3 with an infiltration \nin the lung tissue. Significantly, in 41 patients the pathological process \nwas localized in the right lung.\nResults\nThe main complaints of all hospitalized patients are listed in the \nTable 1.\nIn most cases, there was a chest pain (85.7 per cent); haemoptysis \nwas found less often (9.5 per cent). Dyspnea was noted only in 31 \npatients with pneumothorax; 6 women suffered from infertility. In \nthe anamnesis, 5 patients had uterine myoma, and there was ovary \nendometrial cyst in 2 patients.\nHRCT of the chest detected rounded shadows in the lungs (3 \ncases), infiltrates with thin-walled cavities (6 cases), lung cyst (1 case), \nbullae of various diameter (6 cases), and a mass in the paravertebral \nregion considered as a neurinoma (1 case) (Figure 1). In the same time \nno changes in the lung tissue were detected in 26 of 42 cases (61.9 per \ncent of the patients).\nUnfortunately, a preoperational examination doesn’t allow us to \nsuggest the TES in any case, as CA-125 expression doesn’t indicate \nthe possibility of it either. At the same time, a retrospective analysis of \nthe post-operative data suggested that an essential prerequisite to this \ndiagnosis did exist. \nPre-operational diagnoses were the following: primary spontaneous \npneumothorax in 35 cases, infiltrative pulmonary tuberculosis in 3 \ncases, lung haemosiderosis, neurinoma of mediastinum, lung tumour, \nand lung cyst - each being in one.\nThe surgical intervention was performed in 37 of 42 patients. Of \nthose 35 women with pneumothorax, 30 (85.7 per cent) were operated. \nAtypical lung resection was performed in 27 cases (90 per cent of \nthe patients), costal pleurectomy in 28 cases (93.3 per cent) and the \nresection of the diaphragm tendon centre in 25 cases (83.3 per cent).\nOf 7 patients without pneumothorax 6 were subjected to the \natypical lung resection and 1 to the lobectomy.\nIn all cases а histological examination of the surgical material \nwas performed. Paraffin sections were stained with haematoxylin \nand eosin, alcian blue, and picrofuchsin by van Gieson. Immuno-\nhistochemistry was performed using antibodies to progesterone and \nestrogen receptors as well as mouse monoclonal antibodies to Ki-67 \nand bcl 2 (Dako, Denmark).\nIn correlating clinical and histological data, the TES was diagnosed \nin all cases and may be subdivided into following categories: perforation \nof the right dome of the diaphragm with histologically identfied \nendometrial implants (6 patients); intrapulmonary endometrial \nheterotopias in the form of nodes, infiltrates and cysts (11 patients); \nmultifocal lung and diaphragm lesions (1 patient). A perforation of the \ndiaphragm right dome without histologically identified endometrium \n(“porous diaphragm”) was observed in 24 cases.\nComplaints Patients (n=42)\nabs. number per cent\nChest pain 36 85,7\nDyspnea 31 73,8\nDry cough 21 50,0\nInfertility 6 14,3\nHaemoptysis 4 9,5\nTable 1. Complaints of patients with the thoracic endometriosis syndrome.\n\nDvorakovskaya IV (2017) Pulmonary endometriosis: Clinico-pathological approach to diagnostics and treatment\n Volume 2(1): 3-5\nLung Breath J, 2017          doi: 10.15761/LBJ.1000119\nThe macroscopic assessment of removed lungs detected cysts \nwith dark brown material (6 cases). The walls of the cysts were thick, \ntheir inner surface smooth (5 cases), or with papillary outgrowths (1 \ncase). 5 remaining observations revealed small hemorrhage foci in the \nsubpleural areas. \nThe microscopic examination detected numerous clusters of \nendometrial glands with a cytogenic stroma. The structure of these \nglands corresponded to various phases of the menstrual cycle 9 (viz. \na proliferation or secretion stage) presented in different quantities. \nThe endometrial type of epithelium of the glands was usually \npseudostratified, flattened or columnar; cell nuclei were located at the \ndifferent levels; the cytoplasm contained secret drops; here and there \nsome signs of epithelium desquamation were noted. In the alveolar \nlumina and the lung interstitium hemosiderin deposits were often \nfound. The glandular stroma was represented by elongated cells with \nspindle-shaped nuclei, in some places with decidualization features \n(Figure 2). In 5 cases a cystic transformation of glands was observed \nalong with haemorrhages around them. Some haemosiderin deposits \nand a fibroblastic transformation of a cytogenic stroma were evident \nin the most cases.\nIn all cases the immuno-histochemical study was performed. It \nrevealed the progesterone and estrogen receptors expression in the \ngland epithelium and cytogenic stroma cells (Figure 3 A, B) as well as \nexpression of the oncoprotein bcl-2 in the gland epithelium and moderate \nproliferative activity (Ki-67) in the cytogenic stroma (Figure 3 C).\nShown below are two examples from our observations. \nExample 1. Patient F., 52 years old. The clinical diagnosis was a \ntumor of the right lung lower lobe. Six years before, extirpation of \nthe uterus without appendages was performed on the account of the \nuterus myoma with adenomyosis; the patient suffered from infertility. \n6 years after the surgery there were complaints about periodic aching \npains in the chest, cough and haemoptysis. The radiography of the \nthorax revealed a round shadow of 4 cm in diameter in the lower \nlobe of the right lung. HRCT showed a rounded formation, 4х3х2,5 \ncm in size, heterogeneously structured with well-defined contours. \nThe examination failed to verify the precise diagnosis, so the right \nlower lobectomy was performed. Macroscopically, a “honeycomb” \ntype formation with well-defined contours and small cavities up \nto 0.7 cm filled with thick brown liquid was detected. There was a \ndense homogeneous fibrous tissue between cavities. The histological \nexamination revealed cystic transformed endometrioid glands with a \nproliferating epithelium on their walls as well as a papillae formation \nand a fibrous cytogenic stroma, along with a leiomyomatous hyperplasia \naround glandular structures (Figure 4).\nExample 2: Patient A., 42 years old. Clinical diagnosis was the right-\nside spontaneous pneumothorax. On the first day of the menstrual \ncycle pain in the right half of the chest appeared. It was accompanied \nby a dry cough and a slight dyspnea. Chest radiography revealed a \nright-side pneumothorax with a 50 per cent atelectasis and a shift of \nthe mediastinum to the left. Upon admission to the hospital a right-side \ndiagnostic thoracoscopy was performed with a drainage of the pleural \ncavity. The tendon center of the diaphragm showed perforations \nand endometrial implants (Figure 5). HRCT of the chest revealed no \nchanges in the lung tissue. The right-side videothoracoscopy, resection \nof the diaphragm tendon center and subtotal costal pleurectomy were \nperformed. Macroscopically, some perforations in the tendon centre \nand brownish nodules with well-defined contours up to 0.5 cm were \ndetected. They were located on the pleural diaphragm surface without \npenetrating through it. The histological examination showed some \ncystic endometriod lesions on the fibrous background.\nIn this case, as well as in all others, the onset and the disappearance \nof clinical and radiological symptoms coincided with the beginning \nand the end of the menstrual cycle. Nevertheless, this fact escaped the \nphysisians.\nDiscussion\nAs a clear proof of the words once uttered by the well-known Russian \noncomorphologist Golovin [19,20], the extragenital endometriosis \nconfirms that every tissue is a historically formed stable unity possessing \ncertain properties and morphogenetic potencies, which do not \ndisappear completely even in case of abnormal interrelations between \nan organism and a tumor. This approach is extremely important for \nunderstanding the PE as a pathological process toto coelo. \nIn most of our observations, the endometriosis affected the \ndiaphragm and was accompanied by the pneumothorax with a \ncorresponding symptoms complex, while the pulmonary heterotopia \nFigure 1. HRCT chest scans of patients with pulmonary endometriosis A – lung tissue infiltration; B –small cavities; C – peripheral nodules.\nFigure 2. Pulmonary endometriosis. A - islets of endometrial glands proliferation. In the \nalveolar lumina there are hemosiderin deposits. Haematoxylin and eosin staining (X 100); \nB - proliferating epithelium of the glands with secret drops in cytoplasm. Stroma with \ndecidualization features. Haematoxylin and eosin staining (X 160).\n\nDvorakovskaya IV (2017) Pulmonary endometriosis: Clinico-pathological approach to diagnostics and treatment\n Volume 2(1): 4-5\nLung Breath J, 2017          doi: 10.15761/LBJ.1000119\noccurred rarer being asymptomatic or feigning certain surgical and \nother pathology.\nIt is worth mentioning that the lesion of the left half of the chest \nwas diagnosed only in one case (viz. implants in the left dome of the \ndiaphragm and the left lung), which confirms the fact that TES is the \nright-sided pathology. We suggest that the reason of this selectivity is \nthe fact that the right dome of the diaphragm together with the liver, \nalthough not rigidly bound, works during the breathing like a piston \nproviding a “suction effect”. Supposedly, this is also the reason why it is \nexactly the space under the right diaphragm dome where certain amount \nof the menstrual blood can get from the pelvis. The blood resorption \nis carried out with the active participation of the lymphatic apparatus \nof the peritoneum [21]. Endometrial fragments reach the subpleural \nspace through the lymphatic vessels perforating the diaphragm and \nremain fixed there in most cases. The subsequent necrosis and lysis of \nthe endometrium may lead to the perforation defects. Hypothetically it is \npossible that in rare cases small endometrium fragments reach the superior \nvena cava through the mediastinum lymphatic vessels and then penetrate \ninto the pulmonary parenchyma forming nodes, or cysts.\nThe clinical and morphological hypodiagnostics of the TES is \nconditioned not only by its rarity, but by the lack of the comprehensive \ncomplex analysis and correlation of the anamnestic, clinical, and \nhistological data as well.\nGiven the increasing incidence of the endometriosis, the \npulmonary one among others, it seems essential to include this disease \ninto the differential diagnostics range, particularly where women of \nchildbearing age with the unclear right-sided pulmonary pathology \nand compromised gynecological history are involved. In such cases, it \nis advisable to recruit gynecologists so as to exclude the adenomyosis \nand the pelvic endometriosis. In the case of the obscure recurrent \npulmonary diseases it is imperative to carry out the MRI of the small \npelvis organs.\nOur data allow to determine some important and reliable features \nof the TES as follows: the predominantly right-side localization \nof the disease, the relatively young age of the patients, the cyclic \nrecurrence of the haemoptysis and discomfort or pain in the chest, the \nrecurrent right-side pneumothorax, the correlation of the onset and/\nor regression of the radiological symptoms with the beginning and/or \nend of the menstrual cycle, one or the other of gynecological problems \n(viz. infertility, pelvic pain, algomenorrhea), and surgeries on the pelvic \norgans in the anamnesis. \nThe diagnostic surgery requires an extensive use of the whole \noperation material with cutting out samples for the histological \nexamination of all affected lung areas, since the endometriosis \nmicroscopic features in different, even neighbouring parts of the lung \nmay vary considerably. From the diagnostic standpoint, the essential \nmorphological distinctive feature of the PE is a combination of the \nstability, progression or regression signs within the same or in the \nadjacent samples of the lung tissue. To make the final diagnosis of \nthe TES more reliable, the use of the comprehensive histological and \nimmuno-histochemical methods is required. The precise diagnosis \nof the endometriosis is of great practical importance because it is a \nprerequisite for a selection of the adequate treatment.\nReferences\n1. Tsvelev YV, Abashin VG, et al. (2007) Endometriosis: modern views on the etiology, \nterminology and classification. Vestnik Rus Military Medical Academy 4: 42-47 [In \nRussian]. \nFigure 3. Pulmonary endometriosis: A – expression to progesterone receptors in glandular epithelial cells (X200); B – identical with estrogen receptors (X200); C – Ki-67 expression in the \ncytogenic stroma (X100).\nFigure 4. Pulmonary endometriosis with papillary structures and leiomyomatous \nhyperplasia. Van Gieson staining (X 160).\nFigure 5. Diaphragm lesions revealed in operation. A – perforations in the diaphragm \ntendon center; B – endometrioid implants.\n\nDvorakovskaya IV (2017) Pulmonary endometriosis: Clinico-pathological approach to diagnostics and treatment\n Volume 2(1): 5-5\nLung Breath J, 2017          doi: 10.15761/LBJ.1000119\n2. Olive DL, Schwartz LB (1993) Endometriosis. N Engl J Med 328: 1759-1769. \n[Crossref]\n3. Ozhiganova IN (2009) Endometriosis and endometrioid disease (working standards of \npostmortem examination). SPb. [In Russian]. \n4. Harada M, Osuga Y, Izumi G, Takamura M, Takemura Y, et al. (2011) Dienogest, \na new conservative strategy for extragenital endometriosis: a pilot study. Gynecol \nEndocrinol 27: 717-720. [Crossref]\n5. Bergqvist A (1993) Different types of extragenital endometriosis: a review. Gynecol \nEndocrinol 7: 207-221. [Crossref]\n6. Joseph J, Sahn SA (1996) Thoracic endometriosis syndrome: new observations from an \nanalysis of 110 cases. Am J Med 100: 164-170. [Crossref]\n7. Alifano M, Trisolini R, Cancellieri A, Regnard JF (2006) Thoracic endometriosis: \ncurrent knowledge. Ann Thorac Surg 81: 761-769. [Crossref]\n8. Flieder DB, Moran CA, Travis WD, Koss MN, Mark EJ (1998) Pleuro-pulmonary \nendometriosis and pulmonary ectopic deciduosis: a clinicopathologic and immuno-\nhistochemical study of 10 cases with emphasis on diagnostic pitfalls. Hum Pathol 29: \n1495-1503. [Crossref]\n9. Channabasavaiah AD and Joseph JV (2010) Thoracic endometriosis: revisiting the \nassociation between clinical presentation and thoracic pathology based on thoracoscopic \nfindings in 11 patients. Medone. Baltimore 89: 183-188. [Crossref]\n10. Legras A, Mansuet-Lupo A, Rousset-Jablonski C, Bobbio A, Magdeleinat P, et al. \n(2014) Pneumothorax in women of child-bearing age: an update classification based on \nclinical and pathologic findings. Chest 145: 354-360.11. [Crossref]\n11. Hobbs JE and Bortnick AR. (1940) Endometriosis of the lung; an experimental and \nclinical study. Am J Obstet Gynecol 40: 832-843. \n12. Pichurov AA, OrzheshkovskiÄ  OV, Dvorakovskaia IV, Romanova LA, Ivanishchak \nBE, et al. (2014) [Thoracic endometriosis--the rare pathology in thoracic surgery]. \nVestn Khir Im I I Grek 173: 26-29. [Crossref]\n13. Sampson JA (1927) Peritoneal endometriosis due to menstrual dissemination of \nendometrial tissue into the peritoneal cavity. Am J Obstet. Gynecol 14: 422-469. \n14. Adamyan LV, Kulakov VI, and Andreeva EN (2006). Endometriosis. M., Medizina. \n[In Russian]. \n15. Agarwal N. and Subramanian AA (2010) Endometriosis. Morphology, clinical \npresentations, and molecular pathology. J Lab Physicians 10: 1-9. [Crossref]\n16. IablonskiÄ  PK, Pichurov AA, OrzheshkovskiÄ  OV, Petrun’kin AM, Goncharuk IV \n(2014) [Features of spontaneous pneumothorax in female]. Vestn Khir Im I I Grek 173: \n89-95. [Crossref]\n17. Terada Y, Chen F, Shoji T, Itoh H, Wada H, et al. (1999) A case of endobronchial \nendometriosis treated by subsegmentectomy. Chest 115: 1475-1478.18. Koizumi T, \nInagaki H, et al. (1999) Successful use of gonadotropin-releasing hormone agonist in a \npatient with pulmonary endometriosis. Respiration 66: 544-546. [Crossref]\n18. Golovin DI (1975) Atlas of human tumors. Leningrad, Medizina. [In Russian]. \n19. Abu-Hijleh MF, Habbal OA, Moqattash ST (1995) The role of the diaphragm in \nlymphatic absorption from the peritoneal cavity. J Anat 186: 453-467. [Crossref]\nCopyright: ©2017 Dvorakovskaya IV. 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