{"paper_id":"84beb19b-24cd-4729-9e53-64bdc796625d","body_text":"Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Dec; 161(4):407-412.\n407\nEndometriosis with an aberrant immunophenotype: Challenging differential \ndiagnosis of glandular lesions in the pelvic lymph nodes\nDita Vlckovaa, Jiri Lenzb,c,d, Radek Chvatala, Jan Tihone, Miroslav Kavkae, Lucie Uncapherf\nCase report. We describe an unusual case of pelvic lymph node endometriosis with an aberrant immunophenotype \nmimicking metastasis of adenocarcinoma. A 37-year-old patient with a history of invasive cervical adenocarcinoma \nstage pT1a2 is presented. Due to insufficient loop electrosurgical excision procedure (LEEP) conization, total laparo-\nscopic hysterectomy with pelvic lymphadenectomy was indicated. Intraoperatively, the diagnosis of deep infiltrating \nendometriosis of parametrial ligament and vesicouterine pouch, endometrioma of the left ovary and Allen Master’s \nsyndrome was suspected; the patient had no history or clinical symptoms of endometriosis. A PubMed search of similar \ncases was followed by a comparison to this case and discussion of the differential diagnosis of glandular lesions in the \npelvic lymph nodes is reported.\nResults. Histological investigation showed no residual neoplasia; the diagnosis of endometriosis was confirmed. An \ninteresting microscopic finding was represented by a solitary glandular lesion in one pelvic lymph node. Using im-\nmunohistochemistry, it was demonstrated that there was a complete loss of oestrogen and progesterone receptor \nexpression (unlike parametrial ligament endometriosis). The diagnosis of endometriosis was based on the presence of \nendometrial stroma; malignancy was excluded by bland cytomorphologic features and results of immunohistochemi-\ncal examination.\nConclusions. This type of aberrant of the endometriotic gland immunophenotype has never been presented in the \nscientific literature before. This finding plays a significant role from the pathology standpoint and, perhaps more im-\nportantly, from the clinical standpoint. An asymptomatic patient with a correct diagnosis of lymph node endometriosis \ndid not undergo excessive treatment for false positive diagnosis of metastatic cervical adenocarcinoma.\nKey words: endometriosis, aberrant immunophenotype, oestrogen and progesterone receptors, adenocarcinoma, \ndifferential diagnosis.\nReceived: February 2, 2017; Accepted: July 11, 2017; Available online: August 24, 2017\nhttps://doi.org/10.5507/bp.2017.032\naDepartment of Obstetrics and Gynaecology, Znojmo Hospital, Czech Republic\nbDepartment of Pathology, Znojmo Hospital, Czech Republic\ncCytohisto s.r.o., Breclav, Czech Republic \ndDepartment of Anatomy, Histology, and Embryology, Faculty of Veterinary Medicine, University of Veterinary and Pharmaceutical Sciences, \nBrno, Czech Republic\neDepartment of Surgery, Znojmo Hospital, Czech Republic\nfDepartment of Internal Medicine, Poudre Valley Hospital, Fort Collins, CO, USA\nCorresponding author: Jiri Lenz, e-mail: jiri.lenz@gmail.com\nINTRODUCTION\nEndometriosis represents a common, chronic, estro-\ngen-dependent gynaecologic disorder and is defined as the \npresence of endometriotic glandular and stromal tissue \noutside the uterine corpus\n1-3. It is found in approximately \n5-10% of premenopausal women3,4. \nThe typical symptoms of endometriosis include chron-\nic pelvic pain of varying intensity (50-90% of women), \ninfertility (20-50% of women), dysmenorrhea (50% of \nwomen) and dyspareunia (25-50% of women), thus en-\ndometriosis represents one of the major causes of mor-\nbidity in premenopausal women. Endometriosis of the \nurinary bladder may result in dysuria or hematuria. The \nmain symptoms of bowel endometriosis are dyschezia and \nrectorrhagia\n5,6.\nThe most commonly affected organs are the perito-\nneum, ovaries, fallopian tubes, uterus, vagina, urinary \nbladder and rectosigmoideum. In contrast, it is uncom-\nmon to find endometriosis in sites such as the cica-\ntrice, umbilicus, omentum, lymph nodes, lungs, heart \nor bones\n7,8.\nThe definite cause of endometriosis remains unclear. \nMany theories have been proposed to explain the patho-\ngenesis of endometriosis and to date they all remain \ninconclusive (implantation, regurgitation, metaplastic, \niatrogenic, immunologic, molecular-genetic theory, theory \nof tissue injury, vascular and lymphatic dissemination, \nand stem cell theory) (ref.\n9-13).\nWhile considered a benign disorder, endometriosis \nshares a number of similarities with malignant diseases, \nsuch as an abnormal morphology, deregulated cell growth, \ncellular invasion, neoangiogenesis, DNA aneuploidy, loss \nof heterozygosity, recurrence, migration along the nerve \nbundles, metastatic spread to lymph nodes and distant \norgans\n14.\n\nBiomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Dec; 161(4):407-412.\n408\nMalignant transformation of endometriosis is rare and \naffects 1% of lesions with the ovary being the primary site \nin 79% (ref.\n15-16).\nLymphatic spread of endometriosis to lymph nodes \nhas been documented as a frequent event (25–42%) in \nbowel, rectosigmoid and rectovaginal endometriosis\n17-19.\nLymph node involvement by endometriosis consists \nof isolated endometriotic-like cells (IELC) located in the \nsubcapsular sinus of lymph nodes, representing an early \nstage of involvement, and frank metastatic endometriotic \nlesions\n18.\nAn unusual case of pelvic lymph node endometriosis \nwith an aberrant immunophenotype mimicking metastasis \nof adenocarcinoma is described as follows:\nCASE REPORT\nA 37-year-old woman, smoker, G2P2, with no history \nor symptoms of endometriosis was referred to our depart-\nment for invasive cervical adenocarcinoma stage FIGO \nIA2. Histological examination showed endocervical ad-\nenocarcinoma of the usual type, well differentiated, with \nstromal invasion of 3.5 mm, horizontal spread of 4 mm \nand presence of strong nuclear and cytoplasmic expres-\nsion of p16; the information about vascular invasion was \nnot included in the pathology report. Cervical cytology \nspecimens were repeatedly classified as atypical squamous \ncells of undetermined significance (ASCUS). The diagno-\nsis as well as the initial LEEP conization of the cervix with \na positive margin were performed at another hospital. The \nultrasonographic examination showed normal pelvic area \n(without free fluid or adhesions). The only positive find-\ning was 36x32 mm left ovarian cystic lesion, the so called \nendometrioma. Consequently, the patient underwent a \ntotal laparoscopic hysterectomy with pelvic lymphadenec-\ntomy at this hospital. Intraoperatively, the diagnosis of \ndeep infiltrating endometriosis of parametrial ligament \nand vesicouterine pouch, endometrioma of the left ovary \nand Allen Master´s syndrome was suspected (Fig. 1). The \nhistological examination then confirmed the diagnosis. \nFor classification of endometriosis the revised American \nSociety for Reproductive Medicine (rASRM) score (stage \nIV) and ENZIAN classification (B1) were used.\nHistopathology\nAt the department of pathology 6 separate materials \nwere evaluated: left fallopian tube (1), right fallopian tube \n(2), left ovary (3), uterus including parametrial ligaments \n(4), right pelvic lymph nodes (5), left pelvic lymph nodes \n(6). The Materials were extensively investigated using 102 \ntissue sections stained with hematoxylin-eosin. The uter-\nine cervix was completely processed; no residual epithelial \ndysplasia or invasive neoplasia was found.\nFig. 1. Intraoperative laparoscopic images of endometriosis.\nPlica vesicouterina with white endometriosis lesion (A).\nFossa ovarica – uretherolysis, to free the urether from external pressure of adhesions (B).\nEndometrioma ovarii – chocolate cyst with haemorrhagic content (C).\nPlica vesicouterina with white endometriosis lesion – deperitonealisation (D).\n\nBiomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Dec; 161(4):407-412.\n409\nEndometriosis of the left ovary, uterine cervix, para-\nmetrial ligaments and vesicouterine pouch represented an \nincidental histological finding. \nParticularly interesting in relation to the clinical con-\ntext of cervical adenocarcinoma, was the finding of a \nsolitary gland with cystic dilatation in one of the total \nof 36 regional pelvic lymph nodes. To determine the na-\nture of the lesion a wide range of immunohistochemical \nantibodies was used. The gland stained positively with \ncytokeratin AE1/AE3 (AE1/AE3), cytokeratin 7 (CK7) \nand negatively with cytokeratin 20 (CK20), p16 (unlike \ncervical adenocarcinoma), p53, carcinoembryonic anti-\ngen (CEA), vimentin, oestrogen and progesterone recep-\ntors (ER, PR). Staining with the antibody against CD10 \nrevealed a narrow rim of subjacent stromal cells which \ncoexpressed vimentin, ER and PR (Fig. 2a-c).\nFor comparative reasons, we found immunoprofile of \nparametrial ligament endometriosis with the following \nresults – both stromal and glandular immunonegativity for \np16, p53, CEA and CK20, only stromal immunopositiv-\nity for CD10, only glandular immunopositivity for AE1/\nAE3 and CK7, stromal and glandular immunopositivity \nfor vimentin, ER and PR (Fig. 2d,e).\nA final diagnosis of lymph node endometriosis with \nan aberrant immunophenotype was made.\nDISCUSSION\nThis case report represents a challenging differential \ndiagnosis of glandular lesions in the pelvic lymph nodes. \nIt was necessary to differentiate between metastasis of \ncervical and colorectal adenocarcinoma, lymph node en-\ndometriosis and benign glandular inclusions of müllerian \ntype. Histologically we found a solitary gland with cystic \ndilatation lined by a single layer or pseudostratified co-\nlumnar epithelium with mild nuclear atypia (reactive) and \nlow mitotic rate (without atypical mitotic figures) (Fig. \n2f). The diagnosis of malignancy was excluded through \na lack of significant cellular atypia and mitotic activity, \ninterfollicular location of the gland and an absence of a \ndesmoplastic stromal reaction.\nMüllerian glandular inclusions are found in approxi-\nmately 5% of pelvic lymph node dissections performed for \nstaging of malignant neoplasms such as ovarian or cervi-\ncal carcinoma, or other gynaecological surgeries. These \nare almost always incidental microscopic findings\n20-22. \nThey are most commonly lined by a single layer of cu-\nboidal to columnar tubal-type epithelium (endosalpingio-\nsis), but sometimes by benign endometrioid epithelium\n23, \nmucinous epithelium of endocervical 24-25 or goblet-cell \ntype26, or metaplastic squamous epithelium 27; an admix-\nture of different types of müllerian glands within a lymph \nnode is designated as müllerianosis. Endosalpingiosis is \nsometimes associated with endometriosis\n26. Therefore the \ndistinction between endometriosis and müllerian glandu-\nlar inclusions was based on the presence of endometrial \nstroma.\nUsing immunohistochemistry, a complete loss of oes-\ntrogen and progesterone receptor expression in the endo-\nmetriotic gland in the pelvic lymph node was identified. \nFrom a pathological point of view, this type of aberrant \nFig. 2. Immunohistochemical expression of CD10 in lymph node endometriosis, immunohistochemical expression of oestrogen \nand progesterone receptors in lymph node and parametrial ligament endometriosis and lymph node endometriosis.\nCD10 stains a few endometrial stromal cells adjacent to the gland, confirming the diagnosis of lymph node endometriosis (A) \n(immunohistochemistry, original magnification ×100).\nIn lymph node endometriosis oestrogen (B) and progesterone receptors (C) stain only endometrial stromal cells, endometrial \ngland remains negative (immunohistochemistry, original magnification ×100).\nIn parametrial ligament endometriosis oestrogen (D) and progesterone receptors (E) stain both endometrial stromal cells and \nendometrial gland (immunohistochemistry, original magnification ×100).\nA solitary gland with cystic dilatation lined by a single layer or pseudostratified columnar epithelium with mild reactive atyp ia \nwithout an apparent cuff of stromal endometrial cells (F) (hematoxylin-eosin staining, original magnification x100).\n\nBiomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Dec; 161(4):407-412.\n410\nimmunophenotype is very unusual. This phenomenon is \nnot fully understood but possible causes could be meta-\nplastic processes or transformation in atypical endome-\ntriosis. \nThe result of immunohistochemistry may be affected \nby different methodological approaches. Mouse monoclo-\nnal antibodies, which generally show a higher specificity \nwhen compared with polyclonal antibodies, were used in \nthis case. Maximum effort was applied to prevent the well \nknown technical and interpretative pitfalls of this meth-\nodological approach. All immunohistochemical analyses, \nincluding antigen retrieval, were performed in the same \nlaboratory specialized for immunohistochemistry while \nadhering to standardized protocols. To avoid nonspecific \nbackground staining, the system of positive and negative \ncontrols was used. For confirmation of this unusual find-\ning, immunohistochemistry was repeatedly performed.\nSimilar to this study, in 1994 Brandau and co-workers \ndescribed a case report of an endometriosis in retroperi-\ntoneally situated lymph nodes in a 29-year-old patient. \nThe patient had a cervical carcinoma stage FIGO Ib \nand was treated surgically by radical hysterectomy after \nWertheim-Meigs-Okabayashi with pelvic lymphadenecto-\nmy. Coincidentally endometriosis was found in two lymph \nnodes of the retroperitoneum. The patient had no history \nor clinical symptoms of endometriosis. Endometriosis \ncould not be found in any other parts of the abdomen. \nAdditionally, an aberrant immunophenotype of the endo-\nmetriotic gland in a lymph node with only progesterone \nreceptor expression and loss of oestrogen receptor expres-\nsion was found\n28.\nGlandular lesions in the lymph nodes was first de-\nscribed by Ries in 1897 in patients who underwent a \nhysterectomy and pelvic lymphadenectomy for cervical \ncancer\n29. \nRecently, it has been observed that regional lymph \nnode involvement by endometriosis is a common phe-\nnomenon in women with coincidentally found bowel en-\ndometriosis\n30.\nEndometriotic spread to the lymphatic system is poor-\nly understood and little is known about the molecular \nevents and changes in gene expressions associated with \nthis process. In 2011, Tempfer and colleagues analyzed \nregional lymph node-spread into pelvic sentinel lymph \nnode (PSLN) in a prospective study of 23 patients with \novarian and/or peritoneal endometriosis. They found en-\ndometriotic lesions in 11% and the presence of IELC in \n80% of PSLN (ref.\n31).\nThe study by Bürkle and associates, published in 2013, \nindicates that the spread of endometriosis to PSLN is \naccompanied by different expressions of several genes, \nincluding EPCAM, CDH1 (E-cadherin), CXCR4 and \nCD44. Using quantitative real-time PCR and immuno-\nhistochemistry they analyzed the expression levels of a \npanel of 28 genes previously described to be associated \nwith endometriosis in a series of samples of primary endo-\nmetriotic lesions, IELC-negative PSLN and IELC-positive \nPSLN. Expression of a set of genes (CXCR4, CD68, \nMKI67 and CD44) was found to be higher in IELC- posi-\ntive PSLN than in IELC- negative PSLN, while lowest in \nendometriotic lesions, indicating up-regulation in IELC. \nIn contrast, EPCAM and E-cadherin, which were strongly \nexpressed in endometriotic lesions, were not found to be \nexpressed in IELC- positive PSLN. Study showed that pre-\nrequisites for the transition appear to be the up-regulation \nof the chemokine receptor CXCR4 and CD44 isoforms \n(including CD44v6 isoform), and the loss of expression \nof epithelial markers such as E-cadherin and EPCAM. \nThe next step, establishment of an endometriotic lesion \nwith the lymph node, appears to be accompanied by re-\nexpression of epithelial markers such as cytokeratins, \nE-cadherin and EPCAM (ref.\n32). These data are consis-\ntent with results published by Ruiz et al. who also found \nsignificantly higher CXCR4 expression in endometriotic \nlesions compared to normal endometrium\n33.\nIn 2012 Ji published that macrophages act as a direct \nstructure contributor to lymphatic endothelial walls or \nsecrete a vascular endothelial growth factor (VEGF) to \ninitiate lymphangiogenesis in inflamed or tumor tissues\n34. \nThis finding, together with the fact that endometriosis is \nan inflammatory disorder with an increased concentra-\ntion of macrophages, indicates the possible role of mac-\nrophages in the process of lymph node involvement by \nendometriosis.\nTo our knowledge, the scientific literature does not \ndescribe endometriosis with an aberrant immunopheno-\ntype with complete loss of oestrogen and progesterone \nreceptor expression.\nImmunohistochemical hormonal receptor expression \nin eutopic and ectopic endometrium was analyzed by \nJones and co-workers in a series of 30 women with en-\ndometriosis. They found an increased oestrogen receptor \nexpression in ectopic endometrium from the proliferative \nto the late secretory phase. Compared with the eutopic \nendometrium, the expression in both epithelium and \nstroma of ectopic endometrium was significantly higher \nthroughout the cycle. In contrast, stromal progesterone \nreceptor expression tended to be reduced in ectopic en-\ndometrium compared with eutopic tissue, while epithelial \nprogesterone receptor expression was increased in ectopic \nendometrium only in the late secretory phase\n35. Despite \nthe variable intensity of hormonal receptor expression, \nall cases showed typical immunophenotype with immu-\nnopositivity for both oestrogen and progesterone recep-\ntors. In searching the literature, no publication describing \nheterogeneous expression of estrogen and progesterone \nreceptors in eutopic and ectopic endometrium was found.\nMechsner et al. retrospectively analyzed the frequency \nof endometriotic lesions and disseminated endometriotic-\nlike cells in a series of 108 coincidentally resected lymph \nnodes of 24 patients with endometriosis. Endometriotic \nlesions were detected in 8 out of 24 patients, while dis-\nseminated endometriotic-like cells were found in 17 out of \nthe 24 patients. The study showed typical immunopheno-\ntype in all cases (endometriotic lesions stained positively \nwith ER, PR, CD10 and cytokeratin, endometriotic-like \ncells stained positively with ER and PR) (ref.\n36).\nCurrently, little is known about the mechanism of \n\nBiomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017 Dec; 161(4):407-412.\n411\nrecurrence of endometriosis and its management is not \nefficacious. After surgical and/or medical therapy, endo-\nmetriosis has a high recurrence rate which increases with \nthe length of follow-up. To delay or eliminate recurrence \nis the main goal in the control of this disease\n30. Only a \nlimited number of studies investigated the clinical signifi-\ncance of lymph node involvement by endometriosis with \nsomewhat conflicting results. The most recent study by \nRossini and colleagues from 2016 analyzed correlation \nbetween the severity of endometriosis and lymph node \ninvolvement. The study included 140 cases of colorec-\ntal surgery for intestinal endometriosis; histopathologi-\ncal examination revealed the involvement in 50% of the \ncases. They showed no statistically significant correlation \nbetween the positivity of lymph nodes and the rate of \nintestinal stenosis or the histopathological specimen infil-\ntration rate and depth and the intestinal recurrence rate. \nBased on these results, they hypothesized that lymph node \ninvolvement in intestinal resection specimens does not \nmodify the natural history of the disease\n37. Conversely, \nin the study by Gong and Tempfer, endometriotic cells in \nregional lymph nodes were described as a potential target \nof hormonal stimulation in the postoperative period and \nthey could be a major source of disease recurrence\n30.\nIn 2011 Namkung at al. reported that rectal endome-\ntriosis has the ability to invade adjacent tissue as true \nmalignant tumors and therefore, lymph node involvement \nshould be considered in rectal endometriosis\n38.\nCONCLUSION\nThe coincidence of a cervical adenocarcinoma and \nendometriosis in pelvic lymph nodes may represent a dif-\nferential diagnostic problem. Confirmation of the correct \ndiagnosis requires the use of a wide range of immuno-\nhistochemical antibodies. In the case of an aberrant im-\nmunophenotype with loss of oestrogen and progesterone \nreceptor expression of the endometriotic gland, the find-\ning of CD10-positive endometrial stromal cells and benign \nmorphology of the glandular lesion is essential for proper \ndiagnosis. To our knowledge, this type of aberrant immu-\nnophenotype of the endometriotic gland has never been \npresented in any scientific literature. This finding plays a \nsignificant role from a pathology standpoint and perhaps, \neven more importantly, from the clinical standpoint. The \nasymptomatic patient with the correct diagnosis of lymph \nnode endometriosis did not undergo excessive treatment \nfor false positive diagnosis of metastatic cervical adeno-\ncarcinoma.\nCurrently, little is known about the mechanism of \nlymph node spread of endometriosis. The question re-\nmains whether lymph node endometriosis is a significant \nprognostic factor and will affect the therapeutic approach \nto this disorder in the future. Thus, the presence of lymph \nnode involvement with endometriotic cells may perhaps \npoint toward a systemic aspect of this disease and the \nresection of regional lymph nodes could decrease the re-\ncurrence rate of endometriosis.\nABBREVIATIONS\nAE1/AE3, cytokeratin AE1/AE3; ASCUS, Atypical \nsquamous cells of undetermined significance; CDH1, \nCadherin 1; CD10, Cluster of differentiation 10; CD44, \nCluster of differentiation 44; CD68, Cluster of differ-\nentiation 68; CEA, Carcinoembryonic antigen; CK7, \nCytokeratin 7; CK20, Cytokeratin 20; CXCR4, C-X-C \nchemokine receptor type 4; DNA, Deoxyribonucleic \nacid; EPCAM, Epithelial cell adhesion molecule; ER, \nOestrogen receptors; FIGO, International federation \nof gynecology and obstetrics; G2P2, Gravida 0 para 0; \nIELC, Isolated endometriotic-like cells; IELC- negative \nPSLN, Isolated endometriotic-like cells negative pelvic \nsentinel lymph node; IELC- positive PSLN, Isolated \nendometriotic-like cells positive pelvic sentinel lymph \nnode; LEEP, Loop electrosurgical excision procedure; \nPCR, Polymerase chain reaction; PR, Progesterone re-\nceptors; PSLN, Pelvic sentinel lymph node; p16, protein \n16; p53, protein 53; rASRM, revised American society for \nreproductive medicine score; VEGF, Vascular endothelial \ngrowth factor. \nAuthor contributions: DV: project development, manu-\nscript writing, description of the laparoscopic images; \nJL: manuscript writing, description of the histopathology \nfindings; RCH: description of the laparoscopic images, \ncritically revising the article; JT, MK: literature search; \nLU: linguistic review, manuscript editing.\nConflict of interest statement: The authors state that there \nare no conflicts of interest regarding the publication of \nthis article.\nREFERENCES\n 1. 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