{"paper_id":"9b8447fc-f00a-42ed-81a2-ea0b7c2bb541","body_text":"Adenomyomas are benign tumor-like masses composed of smooth muscle tissue and benign\nendometrioid glands and stroma. These tumors most commonly originate from within the\nuterine corpus. Adenomyomas in extrauterine sites are extremely rare. To the best of\nour knowledge, since it was first reported in 1986, only 14 cases of extrauterine\nadenomyoma have been reported in the English literature, most often occurring in the\novary [ 1 - 12 ].\nIn this report we describe the first case of extrauterine adenomyoma of the liver in\na 29-year-old woman with a history of laparoscopic myomectomy. This is also the\nfirst case of a solitary extrauterine adenomyoma arising in an extra-pelvic site. We\nalso present four major theories from the literature to explain the pathogenesis of\nextrauterine adenomyoma: Müllerian duct fusion defect, sub-coelomic mesenchyme\ntransformation, müllerianosis and endometriosis with prominent smooth muscle\nhyperplasia or metaplasia.\n\nA 29-year-old married non-pregnant woman (P0G0), presented with a 2-year history\nof low back pain that had worsened over the past 2 months. There were no\nremarkable findings on physical examination. The patient had a history of\nuterine leiomyoma and had undergone laparoscopic myomectomy 5 years\npreviously.\nAbdominal ultrasonography revealed a 3.6 × 2.5 cm\nhypoechoic solid mass arising from the posterior right lobe of the liver. No\nother abnormality was detected on pelvic or abdominal ultrasonography. A\nsubsequent CT scan demonstrated a patchy area with slightly lower density in the\nperipheral zone of the posterior right lobe of the liver. Contrast-enhanced CT\nshowed heterogeneous enhancement of the lesion in the arterial phase\n(Figure   1 ). Laboratory investigations, including\nliver function tests and tumor markers (AFP, CEA, CA19-9, and CA125), were\nwithin normal ranges. Serological tests for hepatitis B surface antigen and\nanti-hepatitis C virus antibodies were negative.\nContrast-enhanced CT showed a heterogeneously enhanced mass (arrow)\nin the peripheral zone of the posterior right lobe of the liver.\nExploratory laparotomy revealed a solid, firm mass that was located at the\nsubcapsular region in segment VI of the right liver near the right kidney. The\nrest of the liver and the other pelvic and abdominal organs appeared normal. The\nmass was completely removed by liver tumor resection. A frozen section was\nperformed and interpreted as a spindle cell tumor, but primary and metastatic\nsarcoma of the liver could not be excluded. The patient was doing well and was\nfree from recurrence 5 months after surgery.\nGross inspection of the specimen revealed a\n3.6 × 2.6x1.8 cm white-gray, irregular mass, which was\npartially covered with the hepatic capsule and partially surrounded by normal\nyellow-gray liver tissue. The mass was firm and solid, with scattered cysts and\nfoci of congestion and hemorrhage up to 4 mm in diameter (Figure \n 2 ).\nThe cut surface showed a white-gray mass with cysts and foci of\ncongestion and hemorrhage varying in diameter from 0.5 to\n4 mm.\nHistopathologic examination revealed a subcapsular mass, which had a\nwell-circumscribed margin with the adjacent liver tissue. The mass was\nmultilobular and composed of smooth muscle and benign glands and stroma. The\nsmooth muscle component consisted of whorled intersecting bundles of typical\nsmooth muscle cells with bland nuclei and was focally cellular. However,\nsignificant atypia, mitotic activity or necrosis was not observed. Irregular\nglands and cysts were haphazardly scattered among the smooth muscle bundles. The\nglands and cysts varied in size and shape and were typically lined by a single\nor pseudostratified layer of columnar cells, similar to the normal endometrial\nglands. The endometrioid glands had secretory features and were surrounded by a\nrim of endometrioid stroma. Variable amounts of blood/congestion and hemorrhage,\ndense fibrosis and hyalinization, and hemosiderin-laden macrophages were\nassociated with the endometrioid tissue (Figure   3 ).\nThe adjacent liver tissue was almost normal.\nMicroscopic features (hematoxylin-eosin stain). A , Histopathologic\nexamination revealed a subcapsular mass. The multilobular mass had a\nwell-circumscribed margin with the adjacent liver tissue.  B ,\nIrregular endometrioid glands and cysts were haphazardly scattered among\nthe smooth muscle bundles. Variable amounts of blood/congestion and\nhemorrhage, dense fibrosis, and hemosiderin-laden macrophages were\nassociated with the endometrioid tissue.  C , The whorled\nintersecting smooth muscle component was focally cellular.  D , The\nendometrioid cysts were typically lined by a single layer of columnar\ncells and had secretory features.\nImmunohistochemistry for CK7, ER, PR, SMA, desmin, CD10, S-100, CD34, CD117 and\nHMB45 was performed (Figure   4 ). The endometrioid\nglands were positive for CK7, ER and PR, while the endometrioid stroma\nsurrounding the glands was positive for CD10, ER and PR and negative for SMA and\ndesmin. The smooth muscle component was positive for ER, PR, SMA and desmin and\nnegative for CD10, S-100, CD34, CD117 and HMB45.\nImmunohistochemical staining was performed.  The smooth muscle\ncomponent and the endometrioid tissue were both positive for ER\n (A)  and PR  (B) . The endometrioid stroma surrounding\nthe endometrioid glands was positive for CD10  (C) , while the\nsmooth muscle component was positive for desmin  (D) .\nMoreover, a review of slides from the previous laparoscopic myomectomy specimen\nshowed a typical leiomyoma but no other significant pathology.\n\nEndometriosis, which is defined as the presence of extrauterine endometrioid glands\nand stroma, is a common condition, with a prevalence of 5-10% in the reproductive\nfemale population. Endometriosis typically arises within the pelvis, including the\nfallopian tubes, ovaries and pelvic peritoneum. However, unusual extra-pelvic sites\nof endometriosis have also been reported, including the intestine, appendix,\nabdominal wall, skin, lung, bladder, umbilicus, kidney and even the central nervous\nsystem [ 13 , 14 ]. In an\nextensive review of the English literature, 20 cases of hepatic endometriosis have\nbeen described in premenopausal and postmenopausal women aged from 21-62 years\nold [ 15 - 22 ]. They\nmost often presented with RUQ or epigastric pain, and approximately half had a prior\nhistory of pelvic endometriosis. The most common gross presentation of hepatic\nendometriosis is an endometrioid cyst called an “endometrioma”. The\npathogenesis of hepatic endometriosis is still controversial, and blood/lymphatic\ndissemination is the presumed pathway for intraparenchymal hepatic lesions\n[ 15 , 17 ].\nExtrauterine adenomyomas are defined as circumscribed tumor-like masses consisting of\nsmooth muscle tissue and endometrioid glands and stroma and are similar in most\nrespects to their more common uterine counterparts. They are much less common than\nendometriosis. To the best of our knowledge, only 14 cases of extrauterine\nadenomyoma have been reported in the English literature. Of these, 12 solitary cases\nwere located within the pelvis, with 5 cases arising in the ovaries and 2 cases\narising in the ovarian ligament. The other 2 cases involved multiple sites,\nincluding the ovaries, pelvic wall, mesentery, omentum, ileum and sigmoid colon\n[ 6 ]. In this report, we present the\nfifteenth case of extrauterine adenomyoma and the first case of hepatic adenomyoma.\nThe 15 patients ranged from 29-65 (median 45.5) years of age, and the lesions had\ndiameters of 0.4 cm to 10 cm. Most cases presented with low abdominal and\npelvic pain, and 6 cases had a history of adenomyosis or pelvic endometriosis. The\ngross tumor appearance varied from solid and cystic to entirely solid. Unlike\nendometriosis, extrauterine adenomyoma is characteristically composed of both smooth\nmuscle and endometrioid tissue. Microscopically, the endometrioid tissue is\nintermingled with bundles of smooth muscles. Both the smooth muscle component and\nthe endometrioid tissue were benign in all 15 cases. However, multifocal nuclear\natypia were reported in the smooth muscle component in 2 cases of extrauterine\nadenomyoma [ 5 ], and a focally cellular but\nbenign smooth muscle component was described in our case.\nExtrauterine adenomyomas could easily be misinterpreted as endometriosis or spindle\ncell tumors, including GISTs and leiomyomas/leiomyosarcomas, in intraoperative\nfrozen sections because of insufficient sampling. In the formalin-fixed,\nparaffin-embedded sections of the resected tumor specimen, extrauterine adenomyomas\nshould be first differentiated from other extrauterine lesions that are composed of\na mixture of smooth muscle tissue and heterotopic endometrioid tissue, including\nendometriosis with a smooth muscle component, leiomyomatosis peritonealis\ndisseminata/leiomyomas associated with endometriosis, and uterus-like masses.\nEndometriosis with a smooth muscle component might represent the\nhyperplasia/hypertrophy of indigenous smooth muscle or smooth muscle metaplasia\nwithin endometriosis [ 5 ]. Unlike\nendometriosis with indigenous smooth muscle, the lesion in our case had no obvious\ncontinuity with normal smooth muscle tissue, such as the fallopian tube or bowel\nwall, and was arranged in disorganized short fascicles and bundles. The smooth\nmuscle metaplasia within endometriosis is typically focal and minor, but\nextrauterine adenomyomas show a dominant smooth muscle component and are more\ncircumscribed than endometriosis both grossly and microscopically.\nLeiomyomatosis/leiomyomas have been reported to be associated with endometriosis. In\nmost cases of leiomyomatosis/leiomyomas with endometriosis, the endometriotic cyst\nis either separated from the smooth muscle component or focally and peripherally\nadmixed in the smooth muscle component. Moreover, the smooth muscle component might\nform multiple nodules [ 23 - 27 ]. In contrast, endometrioid glands and cysts are\nscattered within the smooth muscle tissue in adenomyoma, which typically forms a\nsolitary nodule. Uterus-like masses are defined as extrauterine organoid masses in\nvarious sites, including the broad ligament, ovary and small intestine, that are\ncharacterized by a single central cavity lined by endometrium and surrounded by a\nthick wall of smooth muscle, resembling a normal uterus and most likely representing\na particular form of extrauterine adenomyoma [ 6 , 28 - 32 ]. However, adenomyomas\nare typically with dispersed endometrioid glands and cysts and without an organoid\narrangement with a single central cavity. It should be emphasized that the\nhistological findings of these lesions are strikingly similar and may have\noverlapping features. Both adenomyomas with uterus-like features and uterus-like\nmasses with adenomyoma features have been reported [ 2 , 9 ]. Leiomyomatosis with uterus-like\nfeatures and multiple extrauterine adenomyomas/uterus-like masses resembling\nleiomyomatosis have also been described [ 6 , 23 ]. Therefore, these lesions may belong to a\nrelated entity of the same origin. Moreover, the histological distinction between\ntheses lesions is not always clear, and the classification of such lesions may be\nsomewhat arbitrary.\nExtrauterine adenomyoma should also be differentiated from other tumors with\ncombinations of smooth muscle tissue and epithelial components. Hepatobiliary\nadenomyoma is defined as a rare benign tumor-like lesion of the extrahepatic bile\nducts, most often involving the gallbladder. A few cases have also been reported\nelsewhere in the gastrointestinal tract, bile ducts and ampullary region\n[ 33 , 34 ].\nMicroscopically, small glands lined by columnar cells are scattered among the\nfibromuscular stroma. The epithelial component in the hepatobiliary adenomyoma is\nsimilar to that of the normal biliary and pancreatic duct system. In contrast, our\ncase demonstrated no relationship with extrahepatic bile ducts, and the epithelial\ncomponent in our case was endometrioid glands with endometrioid stroma. Leiomyoma,\nGIST and PEComas with entrapped portal tracts might also be excluded. In these\nlesions, intrahepatic bile ducts should be found at the tumor periphery, and no\nendometrioid tissue should be detected. Moreover, GISTs and PEComas typically\ndemonstrate positive immunoreactivity for CD117 and HMB45, respectively.\nAnother differential diagnosis was extrauterine benign metastasizing leiomyoma (BML)\naccording to the immunohistochemical staining (ER/PR positive) and the history of\nmyomectomy. However, BML is most frequently involving the lung [ 35 ], and endometrioid tissue is not observed in\nBML.\nThe morphologic criteria for distinguishing extrauterine benign Müllerian-type\nsmooth muscle component from leiomyosarcoma are not well described. The current\napproach is to apply criteria of the corpus uteri to their extrauterine\ncounterparts, and several potential indicators have been reported to be helpful in\nthe differentiation [ 36 - 39 ].\nThe pathogenesis of extrauterine adenomyomas or uterus-like masses remains uncertain.\nWe present four major theories from the literature. he Müllerian duct fusion\ndefect theory has been proposed to explain the etiology [ 2 , 4 - 6 ]. This theory was supported by cases that have been\nassociated with congenital urogenital abnormalities, including renal agenesis, a\ndouble excretory system and anomalies of the lower genital tract. The sub-coelomic\nmesenchyme transformation theory has become more popular in recent years\n[ 2 , 6 , 7 , 11 , 30 ]. The\nsub-coelomic mesenchyme or secondary Müllerian system is defined as the layer\nof tissue that lies underneath the mesothelial surface of the pelvic and lower\nabdominal peritoneum. According to this theory, extrauterine adenomyomas/uterus-like\nmasses are derived from the sub-coelomic mesenchyme or so-called “secondary\nMüllerian system”, which is supported by cases without congenital\nanomalies and the effectiveness of hormone-related therapy in controlling the\ndisease. In further support of this theory, most cases of extrauterine\nadenomyomas/uterus-like masses arise from pelvic and lower abdominal structures. The\nmüllerianosis (developmentally misplaced Müllerian tissue) theory has\nprovided another explanation for the pathogenesis of extrauterine lesions composed\nof both smooth muscle and endometrioid tissue. Müllerianosis was defined by\nBatt as a heterotopic organoid structure composed of Müllerian rests\n(endometrial tissue, endosalpingeal tissue and/or endocervical tissue) that were\nincorporated within other normal organs during organogenesis [ 40 , 41 ]. The\nmüllerianosis theory was particularly suitable for providing an explanation for\nextrauterine lesions that occurred in unusual sites outside the pelvic and lower\nabdominal cavities, such as the spinal cord [ 42 ]. This theory was further supported by the presence of\nectopic endometrium in human fetuses and lesions that presented in patients without\nevidence of pelvic endometriosis or a history of surgery on the reproductive organs\n[ 40 , 41 ].\nEndometriosis with prominent smooth muscle hyperplasia or metaplasia, which has also\nbeen called endomyometriosis, is the fourth theory to explain pathogenesis\n[ 7 , 43 ]. Due to\nthe different opinions on their origin and pathogenesis, different diagnoses,\nincluding extrauterine adenocarcinoma/uterus-like mass, müllerianosis and\nendomyometriosis, might be reached for the same case by different pathologists\n[ 41 , 42 , 44 ]. The first three theories all agree that these lesions\nare directly derived from multi-potential cells of either the Müllerian or\nsecond Müllerian system. The inducing factors of benign Müllerian lesions\narising from multi-potential cells remain to be determined. Hormonal stimulation was\nconsidered as one of the major inducing factors [ 2 , 6 ]. Because approximately half of\nthe cases of extrauterine adenomyomas, including our case, have a history of surgery\non the reproductive organs 5-22 years previously, surgical stimulation might\nalso be one of the inducing factors [ 2 , 5 , 6 , 9 ]. It is\nmore likely that our case arose from the tissue of the secondary Müllerian\nsystem because no evidence of adenomyosis, pelvic endometriosis, endosalpingiosis,\nendocervicosis or congenital urogenital abnormalities was found, and the lesion was\nlocated at the liver subcapsular region, which was partially covered by the hepatic\nperitoneum.\nThe preoperative diagnosis of extrauterine adenomyoma is difficult because of its\nrarity and non-specific clinical and radiological findings. Primary or metastatic\nmalignancies should be included in the preoperative differential diagnosis.\nMoreover, although the malignant transformation of extrauterine adenocarcinomas has\nnot been reported, it is an uncommon but possible event in endometriosis,\nparticularly in liver endometrioma. For example, one case of in situ adenocarcinoma,\none case of adenosquamous carcinoma and two cases of adenosarcoma were considered to\narise in the setting of liver endometrioma [ 19 - 22 ]. A uterus-like mass associated with endometrioid carcinoma\nhas also been described. Therefore, complete tumor resection might be recommended\nfor extrauterine adenocarcinoma. All 15 reported cases underwent complete tumor\nresection. Only one case with multiple lesions relapsed, which occurred 1 year\nafter tumor resection; the patient received monthly GnRH agonist treatment, and the\ndisease was well controlled during 10 years of follow-up [ 6 ].\n\nIn summary, adenomyomas in extrauterine sites are extremely rare. We present the\nfirst case of an extrauterine adenocarcinoma with a cellular smooth muscle component\ninvolving the liver. Such masses could be easily misinterpreted in the preoperative\ndiagnosis and intraoperative frozen diagnosis. The resected tumor specimen should\nfirst be differentiated from other extrauterine lesions, which are composed of a\nmixture of smooth muscle tissue and heterotopic endometrioid tissue. In this case,\nthe sub-coelomic mesenchyme theory was favored for pathogenesis, and we propose that\ndifferentiation from sub-coelomic mesenchyme to adenocarcinoma may be induced by\nhormonal and/or surgical stimulation.\n\nTo publish this case report and accompanying images, written informed consent was\nobtained from the patient’s family.\n\nThe authors declare that they have no competing interests.\n\nHW W was the main author on the paper, took the clinical images, worked up the case\nand drafted the manuscript. H Z and XW X conducted the immunohistochemical study. ZH\nL was the main pathologist involved in the case, made the finally diagnosis and was\nthe main editor of the body of the text. All authors read and approved the final\nmanuscript.","source_license":"CC-BY-4.0","license_restricted":false}